A novel variant in IFT122 associated with a severe phenotype of cranioectodermal dysplasia.

A 27-year-old multiparous woman conceived her fetus naturally. Early second-trimester ultrasound showed short extremities with systemic subcutaneous edema. The pregnancy was artificially terminated at 19 weeks of gestation because of the abnormalities based on the parents' wishes. The parents desired whole-exome sequencing to detect a causative gene using the umbilical cord and the parents' saliva. Compound heterozygous variants (NC_000003.11(NM_052989.3):c.230 T > G/NC_000003.11(NM_052985.4):c.1178A > T) were identified. We described a fetus with a novel compound heterozygous variant in IFT122. The phenotype of this case was severer than of other types of cranioectodermal dysplasia.

Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant.

Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.

Massive true thymic hyperplasia with osseous metaplasia.

True thymic hyperplasia is defined as an increase in both the size and weight of the gland, while maintaining a normal microscopic architecture. Massive true thymic hyperplasia is a rare type of hyperplasia that compresses adjacent structures and causes various symptoms. Limited reports address the imaging findings of massive true thymic hyperplasia. Herein, we report a case of massive true thymic hyperplasia in a 3-year-old girl with no remarkable medical history. Contrast-enhanced CT revealed an anterior mediastinal mass with a bilobed configuration containing punctate and linear calcifications in curvilinear septa, which corresponded to lamellar bone deposits in the interlobular septa. To our knowledge, this is the first report of massive true thymic hyperplasia with osseous metaplasia. We also discuss the imaging features and etiology of massive true thymic hyperplasia with osseous metaplasia.

A case of germinoma located in the fornix inducing transsynaptic atrophy of the Papez circuit.

Germinoma is a rare CNS germ cell tumor preferentially affecting children and young adults. Intracranial germinomas arise typically in the neurohypophysis and pineal region and occasionally in the basal ganglia and thalamus. Germinomas in the basal ganglia and thalamus are characterized by the ipsilateral cerebral and brainstem hemiatrophy with slowly progressive neurological deficits, which is due to tumor infiltration into the thalamocortical and corticospinal tract and induction of anterograde and retrograde Wallerian degeneration. We report an 11-year-old boy with a mass located in the fornix incidentally discovered on the first work-up of his minor head injury. Imaging findings revealed the ipsilateral atrophy of the mammillary body and the fornix. Stereotactic brain biopsy was performed and the final diagnosis was germinoma. The ipsilateral atrophy of the mammillary body and the fornix implied the transsynaptic degeneration via the Papez circuit. We discuss the unique nature of germinomas and underlying pathological mechanisms.

Imaging of extrapontine myelinolysis preceding central pontine myelinolysis in a case of ornithine transcarbamylase deficiency with hyperammonaemia and hypokalaemia.

Background: Patients with ornithine transcarbamylase deficiency (OTCD) often present with severe hyperammonaemia. We report a case of osmotic demyelination syndrome (ODS) secondary to the treatment of hyperammonaemia due to OTCD, a disease requiring early diagnosis, as it can have a severe prognosis. Case: A girl toddler was brought to the hospital with a complaint of somnolence, presenting with hyperammonaemia and liver failure, and was diagnosed with OTCD. Treatment was started immediately, and the ammonia level returned to the normal range within 24 hours. On days 13-20, another treatment was commenced for re-elevated ammonia levels, which subsequently returned to within the reference range; however, mildly impaired consciousness persisted. Hypokalaemia coincided with temporary intravenous treatment and continuous haemodialysis. T2-weighted magnetic resonance images revealed lesions as high-signal areas in the bilateral putamen on day 11 (extrapontine myelinolysis (EPM)) and in the pons on day 51 (central pontine myelinolysis (CPM)). Consequently, ODS was diagnosed. Conclusion: When interpreting magnetic resonance images of patients under acute treatment for hyperammonaemia due to OTCD, a condition that may be complicated by hypokalaemia, paying attention to findings suggesting EPM may help detect ODS before CPM appears and may improve patient prognosis.

Low donor chimerism may be sufficient to prevent demyelination in adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by white matter degeneration caused by adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene mutations, which lead to an accumulation of very-long-chain fatty acids (VLCFA). Hematopoietic stem cell transplantation (HSCT) is the most effective treatment; however, the ratio of donor-to-recipient cells required to prevent the progression of demyelination is unclear. The proband was diagnosed with the childhood cerebral form of ALD at 5 years of age based on the clinical phenotype, elevated plasma VLCFA levels, and pathogenic ABCD1 mutation c.293C>T (p.Ser98Leu). Soon after the diagnosis, he became bedridden. At 1 year of age, his younger brother was found to carry the same ABCD1 mutation; despite being asymptomatic, at 1 year and 9 months, head magnetic resonance imaging (MRI) showed high-signal-intensity lesions in the cerebral white matter. The patient underwent unrelated cord blood transplantation (UCBT) with a reduced conditioning regimen, which resulted in mixed chimerism. For 7 years after UCBT, the donor chimerism remained low (<10%) in peripheral blood and cerebrospinal fluid. However, even though a second HSCT was not performed, his neurological symptoms and brain MRI findings did not deteriorate. Our case suggests that even a small number of donor cells may prevent demyelination in ALD. This is an important case when considering the timing of a second HSCT.

Adult acampomelic campomelic dysplasia and disorders of sex development due to a reciprocal translocation involving chromosome 17q24.3 upstream of the SOX9 gene.

Balanced chromosomal rearrangements with a breakpoint located upstream of the sex determining region Y-box 9 (SOX9) gene on chromosome 17q24.3 are associated with skeletal abnormalities, campomelic dysplasia (CMPD), or acampomelic campomelic dysplasia (ACMPD). We report on a female patient with a reciprocal translocation of t (11; 17) (p15.4; q24.3), who was diagnosed with acampomelic campomelic dysplasia. The 34-year-old Japanese patient presented with distinct skeletal abnormalities, profound intellectual disability, and female phenotype despite the presence of Y chromosome and the sex determining region Y (SRY) gene. Her menarche started at 33 years and 4 months after hormone therapy of estrogen therapy followed by estrogen progesterone therapy. By conducting whole genome sequencing followed by Sanger sequencing validation, we determined the precise breakpoint positions of the reciprocal translocation, one of which was located 203 kb upstream of the SOX9 gene. Considering the phenotypic variations previously reported among the CMPD/ACMPD patients with a chromosomal translocation in the vicinity of SOX9, the identified translocation was concluded to be responsible for all major phenotypes observed in the patient.

[Volume Measurements of Post-transplanted Liver of Pediatric Recipients Using Workstations and Deep Learning].

PURPOSE: The purpose of this study was to propose a method for segmentation and volume measurement of graft liver and spleen of pediatric transplant recipients on digital imaging and communications in medicine (DICOM) -format images using U-Net and three-dimensional (3-D) workstations (3DWS) . METHOD: For segmentation accuracy assessments, Dice coefficients were calculated for the graft liver and spleen. After verifying that the created DICOM-format images could be imported using the existing 3DWS, accuracy rates between the ground truth and segmentation images were calculated via mask processing. RESULT: As per the verification results, Dice coefficients for the test data were as follows: graft liver, 0.758 and spleen, 0.577. All created DICOM-format images were importable using the 3DWS, with accuracy rates of 87.10±4.70% and 80.27±11.29% for the graft liver and spleen, respectively. CONCLUSION: The U-Net could be used for graft liver and spleen segmentations, and volume measurement using 3DWS was simplified by this method.

Serum and cerebrospinal fluid cytokines in children with acute encephalopathy.

BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). RESULTS: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. CONCLUSION: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.

Prevention of recurrent febrile urinary tract infection in infants: Ultrasonography-oriented approach is more practical than a top-down approach.

BACKGROUND: We previously reported that the top-down approach (TDA) for infants with febrile urinary tract infections (fUTI) could prevent recurrent fUTI (r-fUTI) but produced a high number of false-positives on acute-phase 99m Tc dimercaptosuccinic acid (DMSA) renal scintigraphy. Therefore we compared the ultrasonography-oriented approach (USOA) with TDA from the viewpoint of prevention of r-fUTI. METHODS: The TDA was applied between July 2010 and February 2014 and the USOA was applied between March 2014 and April 2017 in infants with first fUTI. In the USOA group, voiding cystourethrography (VCUG) was performed in the case of abnormality on acute-phase renal bladder ultrasonography (RBUS) or on chronic- phase DMSA, which were performed in all cases. The frequency of r-fUTI was compared between the TDA group and USOA group retrospectively. RESULTS: Seventy-four infants (52 male) and 79 infants (60 male) received TDA or USOA, respectively. No significant differences were found between the TDA and USOA groups in male : female ratio, age in months at initial onset of fUTI, observation period, or number of cases of r-fUTI (TDA group, n = 4; USOA group, n = 5). Seventy-four DMSA scintigraphy and 25 VCUG were carried out in the USOA group, and 111 DMSA scintigraphy and 34 VCUG in the TDA group. CONCLUSIONS: Both USOA and TDA were valid for prevention of r-fUTI, but USOA was superior to TDA with regard to the reduced number of patients undergoing VCUG and DMSA.

Fetal seizure: A video recording and possible etiology.

Fetal seizure is rarely observed. Investigation of both video-recording of seizures and cardiotocography is crucial for a precise diagnosis. Here, we report a case of fetal seizure, and also show a video-ultrasound recording. A 40-year-old woman was admitted to us due to loss of variability in cardiotocography. Ultrasound repeatedly revealed opisthotonus-like and clonic-seizure-like movements. After the abnormal movement, tachycardia up to 210 bpm (postictal tachycardia) was noted. Ultrasound revealed a nuchal cord. A careful investigation of video-ultrasound recording by an epilepsy specialist led to the confirmation of epileptic seizures. At 364/7 , she vaginally gave birth to an infant with an umbilical artery pH of 7.22. The infant died 30 min after birth. No clear video-recordings associated with fetal seizure were available for cases reported so far in the literature. The video provided in this case may be of use for further analyses.

Filar cysts in rare cases may progress in size, particularly when associated with filar lipoma.

PURPOSE: Filar cysts (FCs) are detected incidentally on ultrasonography (US) of the neonatal spine. Their clinical significance has not been widely discussed in the literature because FCs are usually asymptomatic. This study aimed to investigate the clinical features of FCs and distinguish FCs that warrant attention. METHODS: We retrospectively analyzed 396 patients with lumbosacral skin stigmata. Patients who were younger than 1 month old at reference underwent US initially, and those older than 1 month of age underwent magnetic resonance imaging (MRI) at the age of 5-12 months. Patients with an FC in the US underwent subsequent MRI at the age of 5-12 months. Patients with an FC were followed clinically for at least 3 years. RESULTS: FCs were identified in 56 (14.1%) patients. Of the 195 children who underwent US initially, FCs were detected in 49 (25.1%) children. FCs were detected in seven children who underwent MRI initially. Of the 50 children with FCs who underwent MRI at the age of 5-12 months, FCs in 20 patients (40%) showed natural regression and FCs in 30 patients (60%) remained. Two of these 30 patients showed progression in size of the FC, and in both cases, the FCs were associated with a filar lipoma; however, the resected cysts were not neoplastic and did not have obvious clinical significance. CONCLUSIONS: Our study characterizes clinical features of filar cysts. Two-thirds of FCs remained in late infancy. The best sequence of MRI to follow-up FCs is heavily T2-weighted images.

New radiographic standards for age at appearance of the ossification center of the femoral head in Japanese: Appearance at ≤12 months of age is normal in Japanese infants.

BACKGROUND: The ossification center of the femoral head reportedly appears at 7-8 months in 95% infants in the radiographs, but its appearance often delays in Japanese normal infants. The purpose of this study was to survey the age at appearance of the femoral head in the radiographs, evaluate the normal standards of its appearance in Japanese infants, and determine whether the acetabular state affects the time of its appearance. MATERIALS AND METHODS: The patients comprised 436 infants consulted with our institution because of a limitation of abduction in flexion (LA), acetabular dysplasia, or suspected developmental dysplasia of the hip (DDH). Among these patients, 111 infants (222 hips) without radiographic appearance of the femoral head at the first visit were reviewed. The 222 hips were classified into three groups: α angle ≥30° (DDH + group), <30° with LA (DDH-/LA + group), or < 30° without LA (DDH-/LA-group). The age at appearance of the femoral head was investigated in the radiograph in each group. RESULTS: The 50th percentile of the age at appearance of the femoral head was 6 months in the DDH-/LA- and DDH-/LA + groups and 8 months in the DDH + group. The femoral head significantly appeared earlier in the DDH-/LA- and DDH-/LA + groups than in the DDH + group (P < 0.01). The 95th percentile was 12 months in all groups. CONCLUSIONS: Radiographic appearance of the ossification center of the femoral head by 12 months of age is normal in Japanese infants. When the α angle is ≥ 30°, the age at appearance of the femoral head is sometimes delayed.

Absent Ductus Venosus Associated with Partial Liver Defect.

Absent ductus venosus (ADV) is a rare vascular anomaly. We describe a fetus/neonate with ADV with a partial liver defect. A 41-year-old woman was referred to our institute because of fetal cardiomegaly detected by routine prenatal ultrasound, which revealed absence of ductus venosus with an umbilical vein directly draining into the right atrium, consistent with extrahepatic drainage type of ADV. She vaginally gave birth to a 3,096-gram male infant at 38 weeks of gestation. Detailed ultrasound examination revealed a defect of the hepatic rectangular leaf at half a month postnatally. He showed normal development at 1.5 years of age with the liver abnormality and a Morgagni hernia. Liver morphological abnormality should also be considered as a complication of ADV.

A case of severe Alexander disease with de novo c. 239 T > C, p.(F80S), in GFAP.

Alexander disease (AxD) is a progressive neurodegenerative disease caused by a mutation in the glial fibrillary acid protein (GFAP) gene. A 4-year-old boy presented several times with hemiclonic seizures with eye deviation for a few minutes at 28 days after birth. Electroencephalogram showed independent sharp waves in the right and left temporal area. Magnetic resonance imaging showed high intensity T1-weighted images in the white matter of the frontal lobe and basal ganglia. He showed no head control at 4 years of age, and his weight gain was insufficient. He did not show macrocephaly. At 4 years of age, he died of bacterial pneumonia and septic shock. He was diagnosed with AxD, and direct sequencing revealed a de novo known mutation, c. 239 T > C, p.(F80S), in GFAP. Hela and U2-OS cells transfected with GFAP cDNA with c. 239 T > C showed dot-like cytoplasmic aggregation, similar to R239C, a common mutation found in severe infantile AxD. Aggregation in the cytoplasm caused by a GFAP mutation is a hallmark of AxD. Although there is only one previous report of a patient with an F80S mutation, our data support that F80S can cause the severe, infantile form of AxD.

Non-enhanced magnetic resonance imaging versus renal scintigraphy in acute pyelonephritis.

The utility of non-enhanced magnetic resonance imaging (MRI) has not been examined extensively for diagnosing acute pyelonephritis (APN) in children. The aims of this study were to compare non-enhanced MRI with technetium-99 m dimercaptosuccinic acid (99m Tc-DMSA) renal scintigraphy in detecting APN. Six boys and one girl with temperature ≥38°C and positive urine culture received both non-enhanced MRI with whole body diffusion-weighted imaging (DWI) and 99m Tc-DMSA scintigraphy ≤7 days from the fever onset. The sensitivity and specificity of MRI in detecting APN lesions diagnosed on 99m Tc-DMSA scintigraphy were 80% and 100%, respectively. Non-enhanced MRI in children with suspected APN ≤7 days from fever onset might be a suitable replacement for 99m Tc-DMSA scintigraphy for the detection of APN.

Rhinocerebral Mucormycosis With Temporal Artery Thrombosis in an Adolescent Following HLA-haploidentical Stem Cell Transplantation.

Rhinocerebral mucormycosis (RCM) can lead to internal carotid artery thrombosis. Here, we report the first case of RCM with temporal artery thrombosis following HLA-haploidentical stem cell transplantation in an adolescent presenting with low-grade fever, right mandibular pain, and right jaw claudication. This case suggests that RCM can cause temporal artery thrombosis and should be considered as a differential diagnosis in severely immunocompromised patients with maxillary sinusitis presenting with jaw claudication.

Pediatric Primary Alveolar Soft Part Sarcoma of the Bladder.

A 9-year-old girl was diagnosed with primary alveolar soft part sarcoma of the bladder after imaging examinations and transurethral resection (TUR) of the bladder tumor. As a positive surgical margin of the TUR indicated residual tumor cells, we performed a cystourethrectomy to remove the tumor. A continent urinary reservoir for self-catheterization was constructed using the Mainz pouch technique, and an abdominal (umbilical) continent catheterizable stoma using the appendix was performed. For 2.5 years postoperatively, the patient remained free of local recurrence and distant metastasis. The patient's clinical course has been favorable, with good management of clean intermittent self-catheterization.

Top-down approach is possible strategy for predicting breakthrough fUTIs and renal scars in infants.

BACKGROUND: Acute-phase technetium-99 m dimercaptosuccinic acid (DMSA) scintigraphy is recommended for initial imaging in children with febrile urinary tract infection (fUTI). Recently, the importance of identifying patients at risk of recurrent fUTI (r-fUTI) has been emphasized. To clarify the effectiveness of DMSA scintigraphy for predicting r-fUTI in infants, we investigated the relationship between defects on DMSA scintigraphy and r-fUTI. METHODS: Seventy-nine consecutive infants (male: female, 60:19) with fUTI were enrolled in this study. DMSA scintigraphy was performed in the acute phase, and patients with defect underwent voiding cystourethrography and chronic-phase (6 months later) DMSA scintigraphy. Patients were followed on continuous antibiotic prophylaxis (CAP). RESULTS: Defects on acute-phase DMSA scintigraphy were observed in 32 children (40.5%) of 79. The mean follow-up observation period was 17.0 ± 10.1 months. Four patients had r-fUTI (5%). Two of them had defects on DMSA scintigraphy in both the acute phase and chronic phase, and had bilateral vesicoureteral reflux (VUR) grade IV. Two others had r-fUTI without defects on DMSA and did not have VUR. Twelve patients had defect on chronic-phase DMSA scintigraphy and four of them had no VUR. CONCLUSIONS: The top-down approach is a possible method for predicting r-fUTI in infants and does not miss clinically significant VUR. Also, given that the prevalence of r-fUTI was 5% regardless of the presence of defects on acute-phase DMSA, then, in conjunction with genital hygiene and CAP, acute-phase DMSA might be unnecessary if chronic-phase DMSA is performed for all patients to detect renal scar.