Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver?Russell syndrome

Silver?Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient’s intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7?Mb duplication at 15q11.2-q13.1 encompassing the Prader?Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS

A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency

The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1(c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability,sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland.A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency

Growth Hormone Injection Log Analysis with Electronic Injection Device for Qualifying Adherence to Low-Irritant Formulation and Exploring Influential Factors on Adherence

Kei Takasawa,1 Hiroyo Mabe,2 Fusa Nagamatsu,2 Naoko Amano,3 Yuichi Miyakawa,4 Akito Sutani,4 Reiko Kagawa,5 Satoshi Okada,5 Yusuke Tanahashi,6 Shigeru Suzuki,6 Shota Hiroshima,7 Keisuke Nagasaki,7 Sumito Dateki,8 Shigeru Takishima,9 Ikuko Takahashi,10 Kenichi Kashimada1 1Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; 2Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan; 3Department of Pediatrics, Saitama City Hospital, Saitama, Japan; 4Department of Pediatrics, Kawaguchi Municipal Medical Center, Saitama, Japan; 5Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan; 6Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan; 7Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 8Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 9Department of Pediatrics, Soka Municipal Hospital, Saitama, Japan; 10Department of Pediatrics, Akita University Graduate School of Medicine, Akita, JapanCorrespondence: Kei Takasawa, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan, Tel +81-3-5803-5246, Fax +81-3-5803-5249, Email [email protected]: Although the treatment success of long-term growth hormone therapy (GHT) is dependent on maintaining patients’ adherence to treatment, marked variations in adherence levels among children with GHT (eg, 7– 71% nonadherence) have been reported. Barriers to or promoters of GHT adherence have been discussed and investigated, and digital health technologies, such as electronic GH injection devices, may have the potential to assess adherence to GHT more accurately. Thus, we conducted a multicenter, retrospective cohort study using GH injection log analysis of an electronic GH device, GROWJECTOR®L, to qualify adherence and explore the factors influencing adherence.Methods: This study enrolled 41 patients (median[range] age, 5.8[3.0 ~ 17.0] years) with short stature from nine Japanese medical institutions. The injection log data (12– 48 weeks) were read by smartphones and collected into the data center through a cloud server.Results: Although cumulative adherence rates remained higher than 95% throughout the observation period, five (12.2%) patients had low adherence (< 85%). Subsequently, subgroup and logistic regression analyses for exploring factors affecting adherence revealed that self-selection of GH device and irregular injection schedule (ie, frequent injections after midnight) significantly affected adherence rate (p=0.034 and 0.048, respectively). In addition, higher rates of irregular injections significantly affected low adherence (median[range], 11.26[0.79 ~ 30.50]% vs 0.26[0.00 ~ 33.33]%, p = 0.029).Discussion: Our study indicated that injection log analysis using an electronic GH device could detect irregular injection schedules due to a night owl or disturbance in lifetime rhythm affecting low adherence and had significant potential to encourage collaborative monitoring of adherence with healthcare providers and patients themselves/caregivers, along with growing autonomy and shared decision-making. Our study suggests the significance of narrative and personal approaches to adherence of patients with GHT and the usefulness of digital devices for such an approach and for removing various barriers to patient autonomy, leading to improvement and maintenance of adherence.Keywords: GH therapy, digital health technology, shared decision- making, patient autonom

A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome

Takenouchi-Kosaki syndrome (TKS) is a congenital malformation syndrome characterized by severe developmental delay, macrothrombocytopenia, camptodactyly, sensorineural hearing loss, and dysmorphic facial features. Recently, a heterozygous de novo mutation (p.Tyr64Cys) in the CDC42 gene, which encodes a key small GTP binding protein of the Rho-subfamily, was identified in two unrelated patients with TKS. We herein report a third patient with TKS who had the same heterozygous CDC42 mutation. The phenotype of the patient was very similar to those of the two previously reported patients with TKS; however, she also demonstrated novel clinical manifestations, such as congenital hypothyroidism and immunological disturbance. Thus, despite the heterozygous mutation of CDC42 (p.Tyr64Cys) likely being a hot-spot mutation for TKS, its phenotype may be variable. Further studies and the accumulation of patients with CDC42 mutations are needed to clarify the phenotype in patients with TKS and the pathophysiological roles of the CDC42 mutation