First female Korean child with Coffin-Lowry syndrome: a novel variant in RPS6KA3 diagnosed by exome sequencing and a literature review

Coffin-Lowry syndrome (CLS, OMIM # 303600) is a rare X-linked disorder caused by mutations in RPS6KA3. CLS is characterized by facial dysmorphism, digit abnormalities, developmental delays, growth retardation, and progressive skeletal changes in male patients. Females with CLS are variably affected, complicating diagnosis. Here, we describe the clinical and molecular findings in a female Korean child with CLS and review the associated literature. A 5-year-old girl presented with short stature and developmental delays. She had a coarse facial appearance characterized by a prominent forehead, hypertelorism, thick lips, and hypodontia. She also had puffy tapering fingers and pectus excavatum. We performed exome sequencing and identified a novel, likely pathogenic, heterozygous variant, c.326_338delinsCTCGAGAC (p.Val109Alafs*10), in RPS6KA3 (NM_004586.2). This is the first Korean female genetically diagnosed with CLS. In contrast to the delayed bone age reported in previous studies, our patient showed advanced bone age and central precocious puberty. CLS should be considered as a differential diagnosis of short stature, tapering fingers, and developmental delay. We suggest that molecular techniques can be a useful tool for diagnosis of rare disorders such as CLS because such conditions are not simple, and the associated spectrum of phenotypes can vary.

Tailored management of life-threatening complications related to severe obesity in a young adult with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is characterized by hypotonia, distinctive facial features, hyperphagia, obesity, short stature, hypogonadism, intellectual disability, and behavior problems. Uncontrolled hyperphagia can lead to dangerous food-seeking behavior and with life-threatening obesity. Severe obesity is prone to obstructive sleep apnea (OSA) and can lead to cor pulmonale. This study reports on a case involving a 21-year-old man with PWS who developed OSA due to severe obesity, which led to cor pulmonale, a life-threatening complication. Multidisciplinary care provided in the intensive care unit included weight reduction, ventilation support, antipsychotics, sedative drugs, rehabilitation, and meticulous skin care. The patient did recover. To prevent severe obesity in adults with PWS, hyperphagia must be controlled, and the patient must also be managed by an endocrinologist throughout childhood.

Hypertriglyceridemia with acute pancreatitis in a 14-year-old girl with diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is a medically fatal condition in poorly controlled hyperglycemia or newly diagnosed diabetes mellitus. Severe hypertriglyceridemia (HTG) is an uncommon complication of DKA and can be associated with acute pancreatitis (AP). We present the clinical manifestations, laboratory findings, and management of AP associated with HTG in a 14-year-old girl with DKA. The patient, with a 7-year history of type 2 diabetes presented with epigastric pain, 1 month after stopping insulin injection. DKA, severe HTG, and AP were diagnosed based on the laboratory and imaging tests. She recovered from DKA after conventional treatment for DKA, and her triglyceride (TG) level was reduced from 10,867 mg/dL to the normal range after 7 days of admission without antilipid medication. Given that her C-peptide level was not too low and considering her negative diabetes-related antibodies and high TG level, targeted gene panel sequencing was performed on the genes associated with diabetes and HTG. We identified a heterozygous mutation, c.4607C>T (p. Ala1537Val), in ABCC8 related to maturityonset diabetes of the young (MODY) 12. To our knowledge, this is the first reported case of HTG-induced AP with DKA in a patient with MODY. In addition, we reviewed the literature for pediatric cases of HTG with DKA. In patients with DKA, timely awareness of severe HTG related to insulin deficiency is crucial for improving the consequences of AP. We recommend considering AP in all DKA patients presenting with severe HTG to ensure early and proper management.

Prader-Willi syndrome: an update on obesity and endocrine problems

Prader-Willi syndrome (PWS) is a rare complex genetic disorder that results from a lack of expression of the paternally inherited chromosome 15q11-q13. PWS is characterized by hypotonia and feeding difficulty in early infancy and development of morbid obesity aggravated by uncontrolled hyperphagia after childhood and adolescent. Dysmorphic facial features, delayed motor and language development, various degrees of cognitive impairment, and behavioral problems are common in PWS. Without early, intensive nutritional therapy along with behavioral modification, PWS patients develop severe obesity associated with type 2 diabetes, obstructive sleep apnea, right-side heart failure, and other obesity-related metabolic complications. Hypothalamic dysfunction in PWS can lead to several endocrine disorders, including short stature with growth hormone deficiency, hypothyroidism, central adrenal insufficiency, and hypogonadism. In this review, we discuss the natural history of PWS and the mechanisms of hyperphagia and obesity. We also provide an update on obesity treatments and recommendations for screening and monitoring of various endocrine problems that can occur in PWS.

Autosomal Recessive Malignant Infantile Osteopetrosis Associated with a TCIRG1 Mutation: A Case Report of a Neonate Presenting with Hypocalcemia in South Korea

Osteopetrosis refers to a group of genetic skeletal disorders characterized by osteosclerosis and fragile bones. Osteopetrosis can be classified into autosomal dominant, autosomal recessive, or X-linked forms, which might differ in clinical characteristics and disease severity. Autosomal recessive osteopetrosis, also known as malignant osteopetrosis, has an earlier onset, more serious clinical symptoms, and is usually fatal. We encountered a 1-day-old girl who was born full-term via vaginal delivery, which was complicated by meconium-stained amniotic fluid, cephalo-pelvic disproportion, and nuchal cord. Routine neonatal care was provided, in addition to blood tests and chest radiography to screen for sepsis, as well as skull radiography to rule out head injuries. Initial blood tests revealed hypocalcemia, which persisted on follow-up tests the next day. Radiographic examinations revealed diffusely increased bone density and a "space alien" appearance of the skull. Based on radiographic and laboratory findings, the infantile form of osteopetrosis was suspected and genetic testing for identification of the responsible gene. Eventually, a heterozygous mutation of the T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 (TCIRG1) gene (c.292C>T) was identified, making this the first reported case of neonatal-onset malignant osteopetrosis with TCIRG1 mutation in South Korea. Early-onset hypocalcemia is common and usually results from prematurity, fetal growth restriction, maternal diabetes, perinatal asphyxia, and physiologic hypoparathyroidism. However, if hypocalcemia persists, we recommend considering 'infantile of osteopetrosis' as a rare cause of neonatal hypocalcemia and performing radiographic examinations to establish the diagnosis.

GLB1-related disorders: GM1 gangliosidosis and Morquio B disease

GLB1-related disorders comprise two phenotypically unique disorders: GM1 gangliosidosis and Morquio B disease. These autosomal recessive disorders are caused by b-galactosidase deficiency. A hallmark of GM1 gangliosidosis is central nervous system degeneration where ganglioside synthesis is highest. The accumulation of keratan sulfate is the suspected cause of the bone findings in Morquio B disease. GM1 gangliosidosis is clinically characterized by a neurodegenerative disorder associated with dysostosis multiplex, while Morquio B disease is characterized by severe skeletal manifestations and the preservation of intelligence. Morquio B disease and GM1 gangliosidosis may be on a continuum of skeletal involvement. There is currently no effective treatment for GLB1-related disorders. Recently, multiple interventions have been developed and there are several ongoing clinical trials.

Autosomal Recessive Malignant Infantile Osteopetrosis Associated with a TCIRG1 Mutation: A Case Report of a Neonate Presenting with Hypocalcemia in South Korea

Osteopetrosis refers to a group of genetic skeletal disorders characterized by osteosclerosis and fragile bones. Osteopetrosis can be classified into autosomal dominant, autosomal recessive, or X-linked forms, which might differ in clinical characteristics and disease severity. Autosomal recessive osteopetrosis, also known as malignant osteopetrosis, has an earlier onset, more serious clinical symptoms, and is usually fatal. We encountered a 1-day-old girl who was born full-term via vaginal delivery, which was complicated by meconium-stained amniotic fluid, cephalo-pelvic disproportion, and nuchal cord. Routine neonatal care was provided, in addition to blood tests and chest radiography to screen for sepsis, as well as skull radiography to rule out head injuries. Initial blood tests revealed hypocalcemia, which persisted on follow-up tests the next day. Radiographic examinations revealed diffusely increased bone density and a "space alien" appearance of the skull. Based on radiographic and laboratory findings, the infantile form of osteopetrosis was suspected and genetic testing for identification of the responsible gene. Eventually, a heterozygous mutation of the T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 (TCIRG1) gene (c.292C>T) was identified, making this the first reported case of neonatal-onset malignant osteopetrosis with TCIRG1 mutation in South Korea. Early-onset hypocalcemia is common and usually results from prematurity, fetal growth restriction, maternal diabetes, perinatal asphyxia, and physiologic hypoparathyroidism. However, if hypocalcemia persists, we recommend considering 'infantile of osteopetrosis' as a rare cause of neonatal hypocalcemia and performing radiographic examinations to establish the diagnosis.

GLB1-related disorders: GM1 gangliosidosis and Morquio B disease

GLB1-related disorders comprise two phenotypically unique disorders: GM1 gangliosidosis and Morquio B disease. These autosomal recessive disorders are caused by b-galactosidase deficiency. A hallmark of GM1 gangliosidosis is central nervous system degeneration where ganglioside synthesis is highest. The accumulation of keratan sulfate is the suspected cause of the bone findings in Morquio B disease. GM1 gangliosidosis is clinically characterized by a neurodegenerative disorder associated with dysostosis multiplex, while Morquio B disease is characterized by severe skeletal manifestations and the preservation of intelligence. Morquio B disease and GM1 gangliosidosis may be on a continuum of skeletal involvement. There is currently no effective treatment for GLB1-related disorders. Recently, multiple interventions have been developed and there are several ongoing clinical trials.

Nonclassic congenital lipoid adrenal hyperplasia diagnosed at 17 months in a Korean boy with normal male genitalia: emphasis on pigmentation as a diagnostic clue

Congenital lipoid adrenal hyperplasia (CLAH) is one of the most fatal conditions caused by an abnormality of adrenal and gonadal steroidogenesis. CLAH results from loss-of-function mutations of the steroidogenic acute regulatory (STAR) gene; the disease manifests with electrolyte imbalances and hyperpigmentation in neonates or young infants due to adrenocortical hormone deficiencies, and 46, XY genetic male CLAH patients can be phenotypically female. Meanwhile, some patients with STAR mutations develop hyperpigmentation and mild signs of adrenal insufficiency, such as hypoglycemia, after infancy. These patients are classified as having nonclassic CLAH (NCCLAH) caused by STAR mutations that retain partial activity of STAR. We present the case of a Korean boy with normal genitalia who was diagnosed with NCCLAH. He presented with whole-body hyperpigmentation and electrolyte abnormalities, which were noted at the age of 17 months after an episode of sepsis with peritonitis. The compound heterozygous mutations p.Gly221Ser and c.653C>T in STAR were identified by targeted gene-panel sequencing. Skin hyperpigmentation should be considered an important clue for diagnosing NCCLAH.

A case of de novo 18p deletion syndrome with panhypopituitarism

Deletion on the short arm of chromosome 18 is a rare disorder characterized by intellectual disability, growth retardation, and craniofacial malformations (such as prominent ears, microcephaly, ptosis, and a round face). The phenotypic spectrum is wide, encompassing a range of abnormalities from minor congenital malformations to holoprosencephaly. We present a case of a 2-year-old girl with ptosis, a round face, broad neck with low posterior hairline, short stature, and panhypopituitarism. She underwent ventilation tube insertion for recurrent otitis media with effusion. Brain magnetic resonance imaging showed an ectopic posterior pituitary gland and a shallow, small sella turcica with poor visualization of the pituitary stalk. Cytogenetic and chromosomal microarray analysis revealed a de novo deletion on the short arm of chromosome 18 (arr 18p11.32p11.21[136,227–15,099,116]x1). She has been treated with recombinant human growth hormone (GH) therapy since the age of 6 months after diagnosis of GH deficiency. Her growth rate has improved without any side effects from the GH treatment. This case expands the phenotypic spectrum of 18p deletion syndrome and emphasizes the positive impact of GH therapy on linear growth in this syndrome characterized by growth deficiency. Further studies are required to define the genotype-phenotype correlation according to size and loci of the deletion in 18p deletion syndrome and to predict prognosis.

Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center / 소아과

PURPOSE: Pompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center. METHODS: The medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT. RESULTS: Common initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT. CONCLUSION: As ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.

A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets

X-linked hypophosphatemic rickets is caused by loss-of-function mutations in PHEX, which encodes a phosphate-regulating endopeptidase homolog. We report a 26-year-old man with X-linked hypophosphatemic rickets who showed decreased serum phosphate accompanied by bilateral genu valgum and short stature. He had received medical treatment with vitamin D (alfacalcidol) and phosphate from the age of 3 to 20 years. He underwent surgery due to valgus deformity at the age of 14 and 15. Targeted gene panel sequencing for Mendelian genes identified a nonsense mutation in PHEX (c.589C>T; p.Gln197Ter) and a mosaic pattern where only 38% of sequence reads showed the variant allele. This mutation was not found in his mother, who had a normal phenotype. This is a case of a sporadic nonsense mutation in PHEX and up to date, this is the first case of a mosaic mutation in PHEX in Korea.

Etiological trends in male central precocious puberty

PURPOSE: In the present study, the etiological trends in male central precocious puberty (CPP) were examined, and annual distribution was evaluated. METHODS: Seventy-one male CPP subjects who started puberty before 9 years of age were included in this study. All individuals were diagnosed as having CPP at Samsung Medical Center between 2001 and 2016. Chronological age at puberty onset, diagnosis of CPP, bone age, weight (kg), height (cm), puberty stage, brain magnetic resonance imaging findings, testosterone level, basal gonadotropin level, and gonadotropin level after gonadotropin releasing hormone stimulation were analyzed. RESULTS: The 71 patients were divided into 2 groups: idiopathic (group I) and organic (group II) when the lesion was identified as associated with the central nervous system (CNS) or when the patient received chemotherapy for non-CNS tumors before CPP diagnosis, respectively. Forty-four cases (62%) were idiopathic, and 27 (38%) were organic. The proportion of idiopathic CPP was higher than that of organic CPP during the study period. In 51.9% of organic cases, puberty started before 8 years of age, whereas it started after that age in 93.2% of the idiopathic cases. CONCLUSIONS: In the present study, among all male CPP cases, 62% were idiopathic. The probability of idiopathic CPP prevalence was higher in males when the puberty onset was after 8 years of age with no history of cranial radiotherapy or chemotherapy.

De novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism

Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.

2q37 Deletion syndrome confirmed by high-resolution cytogenetic analysis

Chromosome 2q37 deletion syndrome is a rare chromosomal disorder characterized by mild to moderate developmental delay, brachydactyly of the third to fifth digits or toes, short stature, obesity, hypotonia, a characteristic facial appearance, and autism spectrum disorder. Here, we report on a patient with 2q37 deletion presenting with dilated cardiomyopathy (DCMP). Congenital heart malformations have been noted in up to 20% of patients with 2q37 deletions. However, DCMP has not been reported in 2q37 deletion patients previously. The patient exhibited the characteristic facial appearance (a flat nasal bridge, deep-set eyes, arched eyebrows, and a thin upper lip), developmental delay, mild mental retardation, peripheral nerve palsy, and Albright hereditary osteodystrophy (AHO)-like phenotypes (short stature and brachydactyly). Conventional chromosomal analysis results were normal; however, microarray-based comparative genomic hybridization revealed terminal deletion at 2q37.1q37.3. In addition, the patient was confirmed to have partial growth hormone (GH) deficiency and had shown a significant increase in growth rate after substitutive GH therapy. Chromosome 2q37 deletion syndrome should be considered in the differential diagnosis of patients presenting with AHO features, especially in the presence of facial dysmorphism. When patients are suspected of having a 2q37 deletion, high-resolution cytogenetic analysis is recommended.

An atypical case of Noonan syndrome with KRAS mutation diagnosed by targeted exome sequencing

Noonan syndrome (NS) is a genetic disorder caused by autosomal dominant inheritance and is characterized by a distinctive facial appearance, short stature, chest deformity, and congenital heart disease. In individuals with NS, germline mutations have been identified in several genes involved in the RAS/mitogen-activated protein kinase signal transduction pathway. Because of its clinical and genetic heterogeneity, the conventional diagnostic protocol with Sanger sequencing requires a multistep approach. Therefore, molecular genetic diagnosis using targeted exome sequencing (TES) is considered a less expensive and faster method, particularly for patients who do not fulfill the clinical diagnostic criteria of NS. In this case, the patient showed short stature, dysmorphic facial features suggestive of NS, feeding intolerance, cryptorchidism, and intellectual disability in early childhood. At the age of 16, the patient still showed extreme short stature with delayed puberty and characteristic facial features suggestive of NS. Although the patient had no cardiac problems or chest wall deformities, which are commonly present in NS and are major concerns for patients and clinicians, the patient showed several other characteristic clinical features of NS. Considering the possibility of a genetic disorder, including NS, a molecular genetic study with TES was performed. With TES analysis, we detected a pathogenic variant of c.458A > T in KRAS in this patient with atypical NS phenotype and provided appropriate clinical management and genetic counseling. The application of TES enables accurate molecular diagnosis of patients with nonspecific or atypical features in genetic diseases with several responsible genes, such as NS.

Estrogen-mediated Height Control in Girls with Marfan Syndrome

This study evaluated the efficacy of a stepwise regimen of estradiol valerate for height control in girls with Marfan syndrome. Eight girls with Marfan syndrome who had completed estrogen treatment for height control were included. Estradiol valerate was started at a dose of 2 mg/day, and then was increased. The projected final height was estimated using the initial height percentile (on a disease-specific growth curve for Korean Marfan syndrome [gcPFHt]), and the initial bone age (baPFHt). After the estrogen treatment, the projected final height was compared to the actual final height (FHt). The median baseline chronological and bone age were 10.0 and 10.5 years, respectively. After a median of 36.5 months of treatment, the median FHt (172.6 cm) was shorter than the median gcPFHt (181.0 cm) and baPFHt (175.9 cm). In the six patients who started treatment before the age of 11 years, the median FHt (171.8 cm) was shorter than the median gcPFHt (181.5 cm) and baPFHt (177.4 cm) after treatment. The median differences between the FHt and gcPFHt and baPFHt were 9.2 and 8.3 cm, respectively. In two patients started treatment after the age of 11, the differences between FHt and gcPFHt, and baPFHt after treatment were -4 and 1.4 cm, and -1.2 and 0 cm for each case, respectively. A stepwise increasing regimen of estradiol valerate may be an effective treatment for height control in girls with Marfan syndrome, especially when started under 11 years old.

Delayed Diagnosis of Atypical Mowat-Wilson Syndrome

No abstract available.

Disease-specific Growth Charts of Marfan Syndrome Patients in Korea

Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis. These primary skeletal manifestations affect the growth pattern in MFS. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of MFS. We aimed to develop disease-specific growth charts for Korean MFS patients and to use these growth charts for understanding the growth patterns in MFS and managing of patients with MFS. Anthropometric data were available from 187 males and 152 females with MFS through a retrospective review of medical records. Disease-specific growth charts were generated and 3, 25, 50, 75, and 97 percentiles were calculated using the LMS (refers to lambda, mu, and sigma, respectively) smoothing procedure for height and weight. Comparisons between MFS patients and the general population were performed using a one-sample t-test. With regard to the height, the 50th percentile of MFS is above the normative 97th percentile in both genders. With regard to the weight, the 50 percentile of MFS is above the normative 75th percentile in male and between the normative 50th percentile and the 75th percentile in female. The disease-specific growth charts for Korean patients with MFS can be useful for monitoring growth patterns, planning the timing of growth-reductive therapy, predicting adult height and recording responses to growth-reductive therapy.

Elevation of serum creatine kinase during methimazole treatment of Graves disease in a 13-year-old girl and a literature review of similar cases

We report a 13-year-old girl with Graves disease, who showed an increased level of serum creatine kinase (CK) accompanied by myalgia after methimazole (MMI) treatment. This patient developed muscular pain two weeks after MMI administration, along with increased CK levels. The level of thyroid hormone was within the normal range when she showed increased CK levels. After the MMI dose was decreased and levo-thyroxine was added, serum CK levels decreased to normal and the myalgia improved. The pathophysiologic mechanism of this effect has not yet been elucidated. An acute relatively hypothyroid state occurs secondary to antithyroid drug (ATD) administration in chronic hyperthyroidism, which may cause changes in the CK levels. In this report, we present a rare pediatric case, along with a literature review of similar cases. In the initial state of MMI treatment, myalgia should be detected and when it occurs, CK levels should be measured. The clinical strategy of monitoring CK levels with the aim of normalizing thyroid hormones is helpful in case of the development of adverse reactions, such as myalgia, during ATD treatment for Graves disease in children.