Combined Malonic and Methylmalonic Aciduria Diagnosed by Recurrent and Severe Infections Mimicking a Primary Immunodeficiency Disease: A Case Report

Combined malonic and methylmalonic aciduria is a rare genetic disorder caused by ACSF3 biallelic variants that results in impaired protein and fat metabolism and the accumulation of malonic and methylmalonic acids. A 52-day-old infant with a fever and a history of possible meningitis during the neonatal period was hospitalized. Multiple lesions of necrotizing lymphadenitis with abscesses in the left inguinal area were treated by incision and drainage along with appropriate antibiotic therapy, which revealed a methicillin-resistant Staphylococcus aureus infection. At 6 months of age, the patient was admitted with anal abscesses. Due to the increased suspicion of primary immunodeficiency disease, genetic testing was conducted, which revealed ACSF3 biallelic variants inherited from both parents. Urine organic acid analysis revealed elevated levels of malonic and methylmalonic acids. At 29 months, the patient showed normal growth and development without any dietary modifications. He had occasional colds, but severe bacterial infections were absent. The prognosis suggests a benign disease course. Here, we present the first reported case of ACSF3 compound heterozygote variants in Korea.

Three pediatric patients with primary hyperparathyroidism caused by parathyroid adenoma

Primary hyperparathyroidism (PHPT) is a hypercalcemia disorder with inappropriately normal or increased serum parathyroid hormone (PTH) levels resulting from excessive secretion of PTH from one or more of the parathyroid glands. PHPT is uncommon in infants and children, with an estimated incidence of 2–5 cases per 100,000 persons. Patients with PHPT usually present with bone pain, urolithiasis, or nephrolithiasis, as well as nonspecific symptoms such as fatigue and weakness. Asymptomatic hypercalcemia may also be detected incidentally. Only a few cases of pediatric PHPT have been reported in Korea. We present three patients (a 9-year-old girl, a 14-year-old boy, and a 14-year-old girl) with PHPT who manifested variable clinical features of hypercalcemia. The first and second patients each had a parathyroid adenoma and presented with abdominal pain caused by pancreatitis and a ureter stone, respectively. The third patient had an ectopic mediastinal parathyroid adenoma and presented with gait disturbance and weakness of the lower extremities. All of the patients underwent surgical resection of parathyroid adenoma, and their serum calcium levels subsequently normalized without medication.

Thyroid Dyshormonogenesis Due to Dual Oxidase Maturation Factor 2 Mutation as Non-Transient Status of Hypothyroidism

Dual oxidase maturation factor 2 (DUOXA2) is necessary for the enzymatic activity of dual oxidase 2 (DUOX2) to generate hydrogen peroxide production during thyroid hormone synthesis. We describe two Korean children, who were initially suspected to have transient congenital hypothyroidism (CH), but later confirmed to have permanent CH caused by DUOXA2 mutation. Treatment with levothyroxine was discontinued after confirming thyroid-stimulating hormone (TSH) level to be below 10 μU/mL and normal thyroid scan at the first or second trial-off therapy. However, after therapy cessation, TSH elevated to more than 10 μU/mL, and goiter developed in case 2. As a result, levothyroxine was resumed. Next-generation sequencing showed compound heterozygous mutations of DUOXA2 at Y138X and Y246X in case 1 and homozygous mutations of DUOXA2 at Y246X in case 2. In this report, a longer follow-up is recommended even after treatment termination in transient CH, and genetic studies might help assess the permanence of hypothyroidism in cases of mildly elevated TSH after trial-off therapy.

Clinical, endocrinological, and molecular features of four Korean cases of cytochrome P450 oxidoreductase deficiency

Purpose@#Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder caused by mutations in the POR gene encoding an electron donor for all microsomal P450 enzymes. It is characterized by adrenal insufficiency, ambiguous genitalia, maternal virilization during pregnancy, and skeletal dysplasia. In this study, we investigated the clinical, hormonal, and molecular characteristics of patients with POR deficiency in Korea. @*Methods@#This study included four patients with POR deficiency confirmed by biochemical and molecular analysis of POR. Clinical and biochemical findings were reviewed retrospectively. Mutation analysis of POR was performed by Sanger sequencing after polymerase chain reaction amplification of all coding exons and the exon-intron boundaries. @*Results@#All patients presented with adrenal insufficiency and ambiguous genitalia regardless of their genetic sex. Two patients harbored homozygous p.R457H mutations in POR and presented with adrenal insufficiency and genital ambiguity without skeletal phenotypes. The other two patients with compound heterozygous mutations of c.[1329_1330insC];[1370G>A] (p.[I444Hfs*6];[R457H]) manifested skeletal abnormalities, such as craniosynostosis and radiohumeral synostosis, suggesting Antley-Bixler syndrome. They also had multiple congenital anomalies involving heart, kidney, and hearing ability. All patients were treated with physiologic doses of oral hydrocortisone. @*Conclusion@#We report the cases of 4 patients with POR deficiency identified by mutation analysis of POR. Although the study involved a small number of patients, the POR p.R457H mutation was the most common, suggesting founder effect in Korea. POR deficiency is rare and can be misdiagnosed as 21-hydroxylase or 17α-hydroxylase/17,20-lyase deficiency. Therefore, molecular analysis is critical for confirmatory diagnosis.

Efficacy and safety of parenteral vitamin D therapy in infants and children with vitamin D deficiency caused by intestinal malabsorption

Purpose@#Oral supplementation of vitamin D can be inefficient in patients with vitamin D deficiency caused by intestinal malabsorption. This study investigated the efficacy and safety of parenteral vitamin D supplementation in infants and children with vitamin D deficiency caused by intestinal malabsorption. @*Methods@#This study included 11 patients with vitamin D deficiency who were unresponsive to oral vitamin D or were unable to try oral vitamin D therapy due to underlying conditions. All patients were treated with weekly intramuscular injection of cholecalciferol 50,000 IU. Radiological findings and biochemical parameters including serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D3 (25(OH)D3), and parathyroid hormone levels were reviewed retrospectively. @*Results@#Underlying diseases included small bowel atresia (n=3), necrotizing enterocolitis (n=3), congenital megacolon (n=2), chronic intestinal pseudoobstruction (n=1), congenital mesenteric band (n=1), and Crohn disease (n=1). Three patients exhibited rickets on X-ray findings. The mean duration of treatment was 4.8±2.9 weeks. The alkaline phosphatase levels were decreased from 710±650 IU/L to 442±284 IU/L (P=0.143). The 25(OH)D3 level was increased from 6.0±3.4 ng/mL to 50.4±28.8 ng/mL (P=0.008) after 3 months. Two patients with rickets showed improved radiologic findings after parenteral treatment. @*Conclusion@#Parenteral vitamin D therapy was effective and safe in patients with vitamin D deficiency caused by intestinal malabsorption. Long-term follow-up is needed to establish the efficacy of parenteral vitamin D therapy in a large number of patients.

Identification of Potocki–Lupski syndrome in patients with developmental delay and growth failure

PURPOSE@#Potocki–Lupski syndrome (PTLS), is a recently identified, rare genomic disorder. The patients are affected by infantile hypotonia, poor growth and developmental delay. Facial dysmorphism may not be obvious in some patients. PTLS is associated with microduplication at chromosome 17p11.2. In the current study, three Korean patients are reported with their clinical and genetic features.@*MATERIALS AND METHODS@#The clinical findings of each patient were reviewed. Karyotyping and multiplex ligation-dependent probe amplification (MLPA) analyses were done for genetic diagnoses.@*RESULTS@#All the patients did not have the characteristic dysmorphic features, such as broad forehead, triangular face, asymmetric smile and palpebral fissures. On the other hand, all three patients were affected by variable degree of developmental delay, poor oral intake, failure to thrive, and language development disorders. Chromosome 17p11.2 duplication was identified by conventional karyotyping analysis only in one patient, whereas the other confirmed by MLPA analyses.@*CONCLUSION@#Delayed development was mostly commonly observed in our patients without distinct dysmorphic facial features. In this respect, genomic screening in patients with developmental delay would identify more cases with PTLS to understand their long-term clinical courses with the development of adequate psychological and rehabilitation education program.

Pubertal outcomes and sex of rearing of patients with ovotesticular disorder of sex development and mixed gonadal dysgenesis

PURPOSE: Patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis (MGD) usually present with asymmetric gonads and have wide phenotypic variations in internal and external genitalia. The differential diagnosis of these conditions is based on karyotype and pathological findings of the gonads. This study investigated the clinical features at presentation, karyotype, sex of rearing, and pubertal outcomes of patients with ovotesticular DSD and MGD.METHODS: The study comprised 23 patients with DSD who presented with asymmetric gonads. The presenting features, karyotype, sex of rearing, and pubertal outcomes were reviewed retrospectively.RESULTS: All 23 patients presented with ambiguous genitalia at a median age of 1 month (range, 1 day–1.6 years). Müllerian duct remnants were identified in 15 of 23 patients (65.2%). Fourteen patients were diagnosed with ovotesticular DSD, whereas the other 9 were diagnosed with MGD. Eight of 14 patients (57.1%) with ovotesticular DSD were raised as males, while 7 of 9 patients with MGD (77.8%) were assigned as males. One male-assigned patient with ovotesticular DSD changed to female sex at age 20 years.CONCLUSION: Patients with ovotesticular DSD and MGD manifest overlapping clinical presentations and hormonal profiles. It is difficult to determine the sex of rearing and predict long-term pubertal outcomes. Therefore, long-term follow-up is required to monitor spontaneous puberty, sex outcome, and urological and gynecological complications.

An ANKRD11 exonic deletion accompanied by a congenital megacolon in an infant with KBG syndrome

KBG syndrome is an autosomal dominant syndrome presenting with macrodontia, distinctive facial features, skeletal anomalies, and neurological problems caused by mutations in the ankyrin repeat domain 11 (ANKRD11) gene. The diagnosis of KBG is difficult in very young infants as the characteristic macrodontia and typical facial features are not obvious. The youngest patient diagnosed to date was almost one year of age. We here describe a 2-month-old Korean boy with distinctive craniofacial features but without any evidence of macrodontia due to his very early age. He also had a congenital megacolon without ganglion cells in the rectum. A de novo deletion of exons 5–9 of the ANKRD11 gene was identified in this patient by exome sequencing and real-time genomic polymerase chain reaction. As ANKRD11 is involved in the development of myenteric plexus, a bowel movement disorder including a congenital megacolon is not surprising in a patient with KBG syndrome and has possibly been overlooked in past cases.

A novel mutation in XLRS1 gene in X-linked juvenile retinoschisis

X-linked juvenile retinoschisis (XLRS) is characterized by the progressive loss of visual acuity and vitreous hemorrhage. XLRS is caused by a mutation of retinoschisin 1 (RS1) gene at Xp22.13. In the current report, a 2-year-old Korean patient with XLRS was described. The germline deletion of exon 1 was identified in the RS1 gene. Considering X-linked inheritance pattern, validation of a carrier state of a patient's mother is important for the genetic counseling of other family members and for the future reproductive plan. To confirm the carrier state of his mother, the multiplex ligation-dependent probe amplification analysis was done using peripheral leukocytes and found the heterozygous deletion of exon 1 in his mother.

Two Pediatric Patients with Herbal Medicine-Induced Nephrotic Syndrome

Nephrotic syndrome (NS) is a common chronic disease in children; in 90 percent of cases, the condition is primary (idiopathic). Toxic nephropathy can be induced by herbal medicines, and is mainly manifested as tubulointerstitial nephritis and rarely, as glomerulopathy. Here in, we describe two cases of steroid-sensitive NS, which developed after the patients received herbal medicines. A 5-year-old boy and an 8-year-old girl were separately admitted within a short time period with acute onset of generalized edema, proteinuria, hypoalbuminemia, and hypercholesterolemia. Each patient had previously taken herbal medicine, which had been prescribed by different oriental medical clinics for different conditions. The patients were diagnosed with herbal medicine-induced NS and were treated empirically by a standard steroid therapy, with subsequent resolution of their NS. One patient relapsed, but her NS again responded to steroid therapy. We described two unusual cases of prototypical pediatric, steroid-sensitive NS, which was presumed to be minimal-change disease that developed after the administration of herbal medicines. We also reviewed the literature.