Radiological characteristics of skeletal growth in neonates and infants with achondroplasia.

Achondroplasia (ACH) is the most common form of skeletal dysplasia characterized by a rhizomelic short stature. Radiological skeletal findings in pediatric and adult patients with ACH include short long bones, a relatively longer fibula compared to the tibia, a narrow lumbar interpedicular distance, and a hypoplastic iliac wing. Nonetheless, the characteristics of skeletal growth during the neonatal and infantile periods have scarcely been explored. Therefore, this retrospective study aimed to analyze the radiological skeletal growth during the neonatal and infantile periods in 41 Japanese patients with genetically confirmed ACH. The length of long bones in the upper and lower limbs and the lumbar interpedicular distances at L1 and L4 were measured. These parameters showed significant positive correlations with age. The upper segment-to-lower segment ratio in the lower limbs resembled the data of healthy controls from previous reports. The L1/L4 and fibula/tibia ratios increased with age, suggesting that some representative skeletal phenotypes of ACH were less distinct during the neonatal and infantile periods. In conclusion, for the first time, this study radiologically characterized skeletal growth during the neonatal and infantile periods of patients with genetically confirmed ACH.

Association between infant breastfeeding practices and timing of peak height velocity: A nationwide longitudinal survey in Japan.

BACKGROUND: Several studies have discovered an association between infant feeding practices and puberty timing; however, most have involved female cohorts. We investigated the association between infant feeding practices and the timing of peak height velocity in boys and girls. METHODS: Data on infant feeding methods and anthropometric measurements were collected from a nationwide Japanese birth cohort study. The age at peak height velocity (APV, years) was estimated and compared. Subsequently, the effects of breastfeeding duration were analyzed. RESULTS: Of the 13,074 eligible participants, 650, 9455, and 2969 were formula-, mixed-, and exclusively breastfed, respectively. Among girls, the mean APV was significantly later in the mixed-fed (standardized regression coefficient (ß): 0.094, 95% confidence interval (CI): 0.004-0.180) and exclusively breastfed (ß: 0.150, 95% CI: 0.056-0.250) groups than in the formula-fed group. Among boys, the mean APV was not significantly different among the three groups; however, a sensitivity analysis that excluded preterm birth revealed more significantly delayed APV in the breastfed-only group compared to the formula-fed group. Furthermore, a multiple linear regression model revealed that a longer breastfeeding period was associated with later APV. CONCLUSIONS: Infant breastfeeding practices can affect the timing of peak height velocity in both boys and girls. IMPACT: Several studies have discovered an association between infant feeding practices and puberty timing; however, most have involved female cohorts. Age at peak height velocity, derived from longitudinal height measurements, is a useful marker of secondary sexual maturity milestones in boys and girls. A Japanese birth cohort study revealed that breastfed children had a later age at peak height velocity than their formula-fed counterparts; this was more prominent among girls than boys. Furthermore, a duration-effect relationship was observed, where longer breastfeeding duration was associated with a later age at peak height velocity.

Respiratory pathogen trends in patients with Kawasaki disease during the COVID-19 pandemic and respiratory syncytial virus epidemic in Japan.

BACKGROUND: Although the etiology of Kawasaki disease (KD) remains unknown, the most common view is that an infectious agent triggers the activation of the inflammatory cascade in predisposed children. The coronavirus disease 2019 (COVID-19) pandemic has led to the establishment of infection control measures, which reduced the overall incidence of respiratory infections; however, a resurgence of respiratory syncytial virus (RSV) infection occurred in the summer of 2021. This study aimed to examine the relationship between respiratory pathogens and KD during the COVID-19 pandemic and the RSV epidemic in Japan between 2020 and 2021. METHODS: We retrospectively reviewed the medical charts of pediatric patients with KD or respiratory tract infection (RTI) admitted to National Hospital Organization Okayama Medical Center between December 1, 2020, and August 31, 2021. All patients with KD and RTI underwent multiplex polymerase chain reaction testing upon admission. We classified patients with KD into the three subgroups-pathogen-negative, single pathogen-positive, and multi-pathogen-positive-and compared their laboratory data and clinical features. RESULTS: This study enrolled 48 patients with KD and 269 with RTI. Rhinovirus and enterovirus were the most prevalent pathogens in both patients with KD and RTI (13 [27.1%] and 132 patients [49.1%], respectively). The clinical characteristics of the pathogen-negative KD group and the pathogen-positive KD group at diagnosis were similar; however, the pathogen-negative group tended to receive additional treatment, such as multiple courses of intravenous immunoglobulin, intravenous methylprednisolone, infliximab, cyclosporine A, and plasmapheresis, more frequently. The number of patients with KD remained stable when RTI was not prevalent but increased following the surge in RTI with RSV. CONCLUSIONS: An epidemic of respiratory infections led to an increase in the incidence of KD. Patients with respiratory pathogen-negative KD could have greater recalcitrance to intravenous immunoglobulin than those with respiratory pathogen-positive KD.

The clinical course of Rathke's cleft cysts in pediatric patients: impact on growth and pubertal development.

Rathke's cleft cysts (RCCs) are non-neoplastic epithelial lesions in the sellar or suprasellar regions. RCCs are usually asymptomatic; however, some patients experience headaches, visual disturbances, and endocrine disorders. The best treatment for associated endocrinopathy remains elusive. We aimed to investigate the clinical course, magnetic resonance imaging findings, and response to therapy in 10 pediatric patients with RCCs and endocrinopathy. Growth impairment and precocious puberty were observed to be prevalent. One patient with suprasellar extension of RCC underwent surgery, while the others were treated medically. Of the nine patients, seven patients showed stable cyst size, while two patients displayed reduction in cyst size. Hormone replacement and gonadotropin suppression therapy were found to be effective. Imaging and endocrine follow-ups are warranted because of the potential for changes in the cyst size and hormonal changes.

A novel pathogenic variant p.Asp797Val in IFIH1 in a Japanese boy with overlapping Singleton-Merten syndrome and Aicardi-Goutières syndrome.

Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of permanent teeth, and aortic calcification, as well as causing Aicardi-Goutières (A-G) syndrome, which shows progressive encephalopathy, spastic paraplegia, and calcification of basal ganglia. Recently, patients with overlapping syndromes presenting with features of S-M syndrome and A-G syndrome were reported. However, progression of clinical features of this condition has not been fully understood. We report a Japanese boy with a novel pathogenic IFIH1 variant who presented with clinical features of S-M syndrome and A-G syndrome.

Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare connective-tissue disorder characterized by bone fragility. Approximately 90% of all OI cases are caused by variants in COL1A1 or COL1A2. Additionally, IFITM5 variants are responsible for the unique OI type 5. We previously analyzed COL1A1/2 variants in 22 Japanese families with OI through denaturing high-performance liquid chromatography screening, but our detection rate was low (41%). METHODS: To expand the genotype-phenotype correlations, we performed a genetic analysis of COL1A1/2 and IFITM5 in 96 non-consanguineous Japanese OI probands by Sanger sequencing. RESULTS: Of these individuals, 54, 41, and 1 had type 1 (mild), type 2-4 (moderate-to-severe), and type 5 phenotypes, respectively. In the mild group, COL1A1 nonsense and splice-site variants were prevalent (n = 30 and 20, respectively), but there were also COL1A1 and COL1A2 triple-helical glycine substitutions (n = 2 and 1, respectively). In the moderate-to-severe group, although COL1A1 and COL1A2 glycine substitutions were common (n = 14 and 18, respectively), other variants were also detected. The single case of type 5 had the characteristic c.-14C>T variant in IFITM5. CONCLUSION: These results increase our previous detection rate for COL1A1/2 variants to 99% and provide insight into the genotype-phenotype correlations in OI.

Effect of growth hormone therapy on thyroid function in isolated growth hormone deficient and short small for gestational age children: a two-year study, including on assessment of the usefulness of the thyrotropin-releasing hormone (TRH) stimulation test.

Background The relationship between growth hormone (GH)-replacement therapy and the thyroid axis in GH-deficient (GHD) children remains controversial. Furthermore, there have been few reports regarding non-GHD children. We aimed to determine the effect of GH therapy on thyroid function in GHD and non-GHD children and to assess whether thyrotropin-releasing hormone (TRH) stimulation test is helpful for the identification of central hypothyroidism before GH therapy. Methods We retrospectively analyzed data from patients that started GH therapy between 2005 and 2015. The free thyroxine (FT4) and thyroid-stimulating hormone (TSH) concentrations were measured before and during 24 months of GH therapy. The participants were 149 children appropriate for gestational age with GHD (IGHD: isolated GHD) (group 1), 29 small for gestational age (SGA) children with GHD (group 2), and 25 short SGA children (group 3). Results In groups 1 and 2, but not in group 3, serum FT4 concentration transiently decreased. Two IGHD participants exhibited central hypothyroidism during GH therapy, and required levothyroxine (LT4) replacement. They showed either delayed and/or prolonged responses to TRH stimulation tests before start of GH therapy. Conclusions GH therapy had little pharmacological effect on thyroid function, similar changes in serum FT4 concentrations were not observed in participants with SGA but not GHD cases who were administered GH at a pharmacological dose. However, two IGHD participants showed central hypothyroidism and needed LT4 replacement therapy during GH therapy. TRH stimulation test before GH therapy could identify such patients and provoke careful follow-up evaluation of serum FT4 and TSH concentrations.

Novel heterozygous mutation in TBX1 in an infant with hypocalcemic seizures.

Patients with 22q11.2 deletion syndrome have characteristic facial appearance, palate abnormalities, hypoparathyroidism, thymic hypoplasia, and congenital heart disease. The 22q11.2 region includes TBX1 and 30 other genes. Analysis of Tbx1 transgenic mice showed that TBX1 was associated with the 22q11.2 deletion syndrome. In humans, TBX1 mutations have been reported in 22q11.2 deletion-negative patients with velocardiofacial syndrome or DiGeorge syndrome. Genotype-phenotype correlations are not fully understood in these patients. We report the case of an infant with a novel heterozygous TBX1 mutation who experienced hypocalcemic seizures. This patient had no palate abnormalities, cardiac anomalies, or the typical facial appearance observed in 22q11.2 deletion syndrome. The presence of thymic hypoplasia prompted us to perform G-banding, fluorescent in situ hybridization, and subsequent TBX1 analysis. We emphasize the importance of diagnosing thymic hypoplasia in hypocalcemic infants without 22q11.2 deletion for detecting TBX1 mutations.

Sorafenib treatment for papillary thyroid carcinoma with diffuse lung metastases in a child with autism spectrum disorder: a case report.

BACKGROUND: Pediatric papillary thyroid carcinoma frequently presents with lymph node involvement and distant metastases. Sorafenib, an oral multikinase inhibitor, has been used to treat radioactive iodine (RAI) therapy-refractory thyroid carcinoma in adults; however, pediatric experience is limited. Medical procedures and hospitalization for children with autism spectrum disorder may be challenging. CASE PRESENTATION: An 11-year-old boy with autism spectrum disorder and moderate intellectual impairment presented with dyspnea on exertion with thyroid carcinoma and diffuses lung metastases. Total thyroidectomy and adjuvant RAI therapy is the standard treatment; however, the latter therapy was impractical because of his respiratory status and challenging behaviors. He was therefore started on sorafenib 200 mg/day (150 mg/m2/day) and this dosage was increased to 400 mg/day (300 mg/m2/day). The adverse effects were mild and tolerable. After administration of medication, his dyspnea improved and surgery was performed. We attempted to administer RAI therapy after surgery; however, we abandoned it because he had difficulty taking care of himself according to isolation room rules. Thyrotropin suppression therapy was therefore started and sorafenib treatment (400 mg/day) resumed. Follow-up imaging showed regression of pulmonary metastases. The metastases have remained stable for over 24 months on continuous sorafenib treatment without serious adverse events. CONCLUSION: We inevitably used sorafenib as an alternative to standard therapy because of the patient's specific circumstances. Individualized strategies for pediatric cancer patients with autism spectrum disorder are needed.

A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature.

BACKGROUND: Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome. CASE PRESENTATION: A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard deviation). His past medical history was significant for soft cleft palate and bilateral cataracts. He had a flat midface, micrognathia, and limitations in bilateral elbow flexion. Radiographs showed mild spondyloepiphyseal dysplasia. Initially, we suspected Marshall syndrome, but no mutation was identified in COL11A1. At 8 years old, his height was 116.2 cm (-1.89 standard deviation), and his orofacial characteristics appeared unremarkable. We analyzed the COL2A1 gene and found a novel heterozygous mutation (c.1142 G > A, p.Gly381Asp). CONCLUSIONS: In this case report, we identify a novel missense mutation in the COL2A1 gene in a patient with Stickler syndrome type 1, and we describe age-related changes in the clinical phenotype with regard to orofacial characteristics and height. Genetic analysis is helpful for the diagnosis of this clinically variable and genetically heterogeneous disorder.

Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary Coproporphyria.

Genetic mutation of the coproporphyrinogen oxidase (CPOX) gene causes either hereditary coproporphyria (HCP) or harderoporphyria. HCP, a rare hepatic porphyria, causes acute attacks after puberty and rarely accompanies cutaneous symptoms. In contrast, harderoporphyria is an erythropoietic porphyria that represents photosensitivity and hemolytic anemia from the neonatal period. In patients with harderoporphyria, the p.Lys404Glu mutation is found in the homozygous or compound heterozygous state with another mutation, and a marked increase in harderoporphyrin is observed. This report describes a neonate with symptoms of erythropoietic harderoporphyria (photosensitivity of the skin, hemolytic anemia, and jaundice). However, the pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. We found a heterozygous, novel, four-base pair deletion in exon 7 of the CPOX gene, although other mutations including the p.Lys404Glu mutation in CPOX were not found. By unknown etiology, our patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development. Based on genetic mutation of the CPOX gene and information from a previous similar case report, we consider that neonatal-onset HCP is a variant of HCP.

Clinical Epidemiology and Treatment of Febrile and Afebrile Convulsions With Mild Gastroenteritis: A Multicenter Study.

BACKGROUND: We investigated features and responses to treatment in patients with febrile and afebrile convulsions with mild gastroenteritis and characterized convulsions with rotavirus and norovirus gastroenteritis. METHODS: We conducted a prospective, observational study to evaluate patients with febrile and afebrile convulsions with mild gastroenteritis who were hospitalized between November 2011 and March 2014 at 13 facilities in the National Hospital Organization. We classified the patients into two groups: presence or absence of fever. We investigated the background, clinical and laboratory characteristics, viral antigen in stool, and efficacy of anticonvulsant drugs. RESULTS: Of 126 patients enrolled in this study, 50 were febrile (Fc group) and 76 were afebrile (aFc group). A family history of febrile seizures was significantly more frequent in the Fc group than in the aFc group (28.0% vs 9.2%, P = 0.005). Clinical characteristics were similar between the rotavirus and norovirus groups, but fever was significantly more frequent in the rotavirus group (46.2% vs 8.3%, P < 0.001). Serum sodium levels were significantly negatively related to the number of seizures in the aFc group (ß = -0.13; 95% confidence interval, -0.24, -0.03; P = 0.01). Carbamazepine was significantly more efficacious than diazepam suppositories in the aFc group (odds ratio = 49.3, 95% confidence interval, 2.35, 1037; P = 0.01). CONCLUSION: Febrile convulsions with mild gastroenteritis show characteristics of both febrile seizures and convulsions with mild gastroenteritis. Carbamazepine is optimal for convulsions with mild gastroenteritis. Clinical features of convulsions with rotavirus and norovirus gastroenteritis are similar, except for fever. Serum sodium levels may play a major role in the onset of convulsions with mild gastroenteritis.

Three cases of Japanese acromicric/geleophysic dysplasia with FBN1 mutations: a comparison of clinical and radiological features.

Acromicric dysplasia (AD) and geleophysic dysplasia (GD) are rare skeletal dysplasias characterized by short stature, acromelia, joint contracture, hepatomegaly, hoarseness and respiratory distress. Compared with GD, AD presents with milder clinical and radiological features. Radiological findings of AD and GD consist of shortened tubular bones of the hands and feet, and deformed capital femoral epiphyses. The genetic cause of AD and some cases of GD was shown to be mutations in the transforming growth factor (TGF) ß-binding protein-like domain 5 of the fibrillin 1 gene (FBN1), which is also mutated in Marfan syndrome. In the present study, we report and compare the highly varied clinical and radiological features of three Japanese AD/GD children. Our patients, harboring FBN1 mutations p.Tyr1699Cys, p.Ser1750Arg, and p.Gly1762Ser, shared common clinical symptoms such as severe short stature, acromelia and hepatomegaly. Short tubular bones of hands and deformities of femur heads are common radiological features of our patients.

Urinary Cross-linked N-terminal Telopeptide of Type I Collagen Levels of Infants with Osteogenesis Imperfecta and Healthy Infants.

The urinary cross-linked N-terminal telopeptide of type I collagen (uNTx) levels in infantile osteogenesis imperfecta (OI) have not been well studied. Here we investigated the levels of uNTx in infants with OI and healthy infants. We collected spot urine samples from 30 infants with OI (male/female, 14/16; Sillence classification, I/II/III/IV: 15/3/6/6; age, 5.2±4.4 months) and 120 healthy infants (male/female, 75/45; age, 5.1±4.1 months) for the measurement of uNTx levels. The uNTx levels of the OI infants were significantly lower than those of the healthy infants (mean±SD, 1,363.7±530.1 vs. 2,622.2±1,202.6 nmol BCE/mmol Cr; p＜0.001). The uNTx levels of the infants with type I OI were significantly lower than those of the age-matched healthy infants, although an overlap was observed between the 2 groups. Among the 1-month-old infants, the uNTx levels of the infants with types I, III or IV OI were significantly lower than those of the healthy infants, without overlap (1,622.5±235.8 vs. 3,781.0±1,027.1 nmol BCE/mmol Cr; p＜0.001). These results indicate that uNTx levels are significantly lower in infants with OI than in healthy infants, and they suggest that uNTx might be useful as a reference for diagnosing OI.