Nobutake Matsuo

Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features

Although clinical features in Turner syndrome have been well defined, underlying genetic factors have not been clarified. To deduce the factors leading to the development of clinical features, we took the following four steps: (1) assessment of clinical features in classic 45,X Turner syndrome; (2) review of clinical features in various female sex chromosome aberrations (karyotype-phenotype correlations); (3) assessment of factors that could lead to Turner features; and (4) correlation of the clinical features with the effects of specific factors. The results indicate that the clinical features in 45,X and in other female sex chromosome aberrations may primarily be determined by: (1) degree of global non-specific developmental defects caused by quantitative alteration of a euchromatic or noninactivated region; (2) dosage effect of a pseudoautosomal growth gene(s), a Y-specific growth gene(s), and an Xp-Yp homologous lymphogenic gene(s); and (3) degree of chromosome pairing failure in meiocytes that are destined to develop as oocytes in the absence of SRY.

Mutations in the PIT-1 gene in children with combined pituitary hormone deficiency

Pit-1 is a pituitary-specific transcription factor that binds to and transactivates promoters of growth hormone and prolactin genes. In three unrelated Japanese children with combined pituitary hormone deficiency, we identified three point mutations in the Pit-1 gene, Pro24Leu, Arg143Gln, and Arg271Trp, located on the major transactivation region, POU-specific domain, and POU-homeodomain, respectively.

Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome.

Documentation of maternal uniparental disomy of chromosome 7 in 10% of patients with Russell-Silver syndrome (RSS), characterized by prenatal and postnatal growth retardation and dysmorphic features, has suggested the presence of an imprinted gene on chromosome 7 whose mutation is responsible for the RSS phenotype. Human GRB10 on chromosome 7, a homologue of the mouse imprinted gene Grb10, is a candidate, because GRB10 has a suppressive effect on growth, through its interaction with either the IGF-I receptor or the GH receptor, and two patients with RSS were shown to have a maternally derived duplication of 7p11-p13, encompassing GRB10. In the present study, we first demonstrated that the GRB10 gene is also monoallelically expressed in human fetal brain tissues and is transcribed from the maternally derived allele in somatic-cell hybrids. Hence, human GRB10 is imprinted. A mutation analysis of GRB10 in 58 unrelated patients with RSS identified, within the N-terminal domain of the protein, a P95S substitution in two patients with RSS. In these two cases, the mutant allele was inherited from the mother. The fact that monoallelic GRB10 expression was observed from the maternal allele in this study suggests but does not prove that these maternally transmitted mutant alleles contribute to the RSS phenotype.

Phenotypic discordance in monozygotic twins with 22q11.2 deletion

We report on male monozygotic twins with 22q11.2 deletion and discordant phenotypes. The twins had twin-to-twin transfusion syndrome. Twin 1, the smaller of the pair, had Tetralogy of Fallot, a characteristic facial appearance, swallowing dysfunction, anal atresia, short stature, and mental retardation, whereas twin 2 had a characteristic facial appearance but no other signs of the 22q11 deletion syndrome. Fluorescence in situ hybridization analysis showed a microdeletion on chromosome 22q11.2 in both twins. Zygosity analysis gave a probability of monozygosity greater than 99.999%. These observations indicate that environmental factors or postzygotic events play a role in the phenotypic variability in the twins.

Isoform-Specific Imprinting of the Human PEG1/MEST Gene

We thank Mr. Taichi Suzuki, from Tokyo Technical College, for excellent laboratory assistance. This work was supported, in part, by a grant from the Pharmacia-Upjohn Fund for Growth & Development Research.

Standardized centile curves of body mass index for Japanese children and adolescents based on the 1978–1981 national survey data

Background: The prevalence of overweight among Japanese children and adolescents has steadily increased during the last 20 years. Thus, we utilized the 1978–1981 data collected by the Japanese Ministry of International Trade and Industry to construct reference curves of body mass index (BMI) for contemporary Japanese children and adolescents. Methods: BMI reference values were derived using the LMS method as based on height and weight data from the cross-sectional national survey of Japanese children and adolescents conducted in 1978–1981 (14 012 boys and 13 781 girls, aged 1.5–18.5 years). Results: The Japanese BMI reference curves were constructed for clinical use. The centile values at the upper end of the spectrum apparently differed in British, Dutch, Japanese, and US children and adolescents. In contrast, the centile values at the lower end of the spectrum nearly overlapped with each other in the four populations. Conclusions: Overweight is concentrated in a subgroup of children and does not occur across the entire population of British, Dutch, Japanese, and US children, indicating a subgroup of genetically and/or environmentally more susceptible children in each country. Résumé. Arrière plan: La prévalence du surpoids chez les enfants et adolescents japonais, s’est régulièrement accrue au cours des vingt dernières années. C’est pourquoi nous avons utilisé les données recueillies par le Ministère du Commerce International et de l’Industrie entre 1978 et 1981, afin de construire ds courbes de référence de l’indice de masse corporelle (IMC) des enfants et adolescens japonais contemporains. Méthodes: Les valeurs d’IMC de référence ont été obtenues par la méthode des moindres carrés à partir de données transversales de poids et de stature récoltées entre 1978 et 1981 sur 14012 garçons et 13781 filles âgés de 1,5 à 18,5 ans. Résultats: Les courbes de référence de l’IMC des japonais ont été construites en vue d’un usage clinique. Les valeurs les plus élevées des centiles diffèrent apparemment de celles des enfants et adolescents britanniques, néerlandais et des Etats–Unis. Au contraire, les valeurs de centiles les plus basses se chevauchent presque dans les quatre populations. Conclusions: Le surpoids est concentré dans un sous groupe d’enfants et ne s’observe pas dans l’ensemble de la population des enfants britanniques, néerlandais, japonais et des Etats–Unis, ce qui signale l’existence d’un sous groupe plus susceptible dans chaque pays, que ce soit génétiquement et/ou pour des causes environnementales. Zusammenfassung. Hintergrund: Die Prävalenz von Übergewicht bei Japanischen Kindern und Jugendlichen ist in den letzten 20 Jahren stetig gestiegen. Aus diesem Grunde verwendeten wir Daten, die in den Jahren 1978--1981 vom Japanischen Ministerium für Internationalen Handel und Industrie (Japanese Ministry of International Trade and Industry) gesammelt worden waren, um BMI-Referenzkurven für heutige Japanische Kinder und Jugendlichen zu konstruieren. Methoden: BMI-Referenzwerte wurden mit LMS-Methode basierend auf Körperhöhen- und Gewichtsdaten der nationalen Querschnittsstudie an Japanischen Kindern und Jugendlichen der Jahre 1978--1981 (14012 Knaben und 13781 Mädchen im Alter von 1,5–18,5 Jahren) entwickelt. Ergebnisse: Die Japanischen BMI-Referenzkurven wurden für den klinischen Gebrauch konstruiert. Die Perzentilwerte aus dem oberen Ende des Spektrums unterschieden sich offensichtlich von Britischen, Niederländischen, Japanischen und US-Amerikanischen Kindern und Jugendlichen. Dagegen überlappten sich die Perzentilen weitgehend am unteren Ende des Wertespektrums mit den denen der anderen vier Populationen. Zusammenfassung: Übergewicht findet sich vorwiegend in einer Untergruppe von Kindern und kommt nicht in der gesamten Population von Britischen, Niederländischen, Japanischen und US-Amerikanischen Kindern vor, was darauf hindeutet, dass es eine Untergruppe von genetisch und/oder umweltbedingt empfindlicheren Kindern in jedem dieser Länder gibt. Resumen. Antecedentes: La prevalencia de sobrepeso entre los niños y adolescentes japoneses ha aumentado de manera continua durante los últimos 20 años. Por ello, se han empleado los datos recogidos entre 1978--1981 por el Ministerio Japonés de Comercio Internacional e Industria, para construir curvas de referencia del índice de masa corporal (IMC) para los niños y adolescentes actuales. Métodos: Los valores de referencia del IMC se obtuvieron mediante el método LMS, utilizando datos de la estatura y peso procedentes de la encuesta nacional transversal de niños y adolescentes japoneses, realizada entre 1978--1981 (14.012 chicos y 13.781 chicas, de entre 1,5 y 18,5 años de edad). Resultados: Las curvas de referencia del IMC de los japoneses se construyeron para uso clínico. Los valores centilares en el extremo superior del espectro diferían aparentemente entre los niños y adolescentes británicos, holandeses, japoneses y estadounidenses. Por el contrario, los valores centilares en el extremo inferior del espectro se solapaban en las cuatro poblaciones. Conclusiones: El sobrepeso se concentra en un subgrupo de niños y no se encuentra en toda la población de niños británicos, holandeses, japoneses y estadounidenses, lo que apunta a la existencia de un subgrupo de niños más susceptible genética y/o ambientalmente en cada país.

Hyper-IgM immunodeficiency with disseminated cryptococcosis

We describe two siblings with X‐linked hyper‐IgM immunodeficiency. One patient developed disseminated cryptococcosis. Co‐culture of this patients T cells with normal B cells suppressed IgC and IgA production. The CD40 ligand gene of one patient was examined and contained a nonsense mutation at nucleotide 475. CD40 ligand is a membrane protein which is expressed on activated T cells and induces B‐cell proliferation. These results suggest that there is a defect in T‐ and B‐cell interactions in this immunodeficiency syndrome. It is also possible that patients with this syndrome are predisposed to cryptococcal infections.

Hepatic Dysfunction in Two Sibs With Alström Syndrome: Case Report and Review of the Literature

Alström syndrome is an autosomal recessive disorder (MIM No. *203800) characterized by retinal degeneration, obesity, deafness, noninsulin-dependent diabetes mellitus, and nephropathy. We report two sibs with Alström syndrome and hepatic dysfunction. The first sib developed elevations in liver enzymes at 29 years of age. Liver biopsy showed fatty liver, lymphocytic infiltration, and piecemeal necrosis. The second sib had had elevated gamma-glutamyltransferase levels since she was 10 years old. She developed ascites, esophageal varices, and splenomegaly in her twenties. Cirrhosis was confirmed by autopsy; the patient was 26 years of age at death. Three Alström syndrome patients with hepatic dysfunction have been documented previously. No specific cause was identified for liver disease in any of the patients, including ours. Hepatic dysfunction appears to be a manifestation of Alström syndrome.

The association of hypopituitarism with small pituitary, invisible pituitary stalk, type 1 Arnold-Chiari malformation, and syringomyelia in seven patients born in breech position: a further proof of birth injury theory on the pathogenesis of “idiopathic hypopituitarism”

We report seven cases of hypopituitarism all having a history of breech delivery, asphyxia at birth, and syringomyelia. A small pituitary gland was found on MRI or CT in six cases, invisible pituitary stalk on MRI in five cases, and type 1 Arnold-Chiari malformation in six cases. A constellation of these abnormalities are best explained by traction of brain and spinal cord of the subjects exerted during breech delivery and further support the primary role of birth trauma in the genesis of “idiopathic hypopituitarism”.

Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene

Abstract X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk α subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.