Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.

Maternal side effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia.

UNLABELLED: Prenatal treatment of virilizing congenital adrenal hyperplasia in female fetuses via maternal dexamethasone (Dex) therapy (1-1.5 mg/day) from first trimester to birth was associated with excessive weight gain (47-56 pounds at 35-37 weeks gestation), Cushingoid facial features, severe striae resulting in permanent scarring, and hyperglycemic response (8-11.7 nmol/L) to oral glucose administration in all our experience (three cases). Other symptoms included hypertension, gastrointestinal intolerance, or extreme irritability. Previous pregnancies were uncomplicated by these problems. In each case, first or second trimester amniotic fluid 17-hydroxyprogesterone (17OHP, 17-41 nmol/L; normal less than 0.4 nmol/L), androstenedione (22-31 nmol/L, normal less than 5 nmol/L), and testosterone levels (0.54-0.7 nmol/L, normal less than 0.4 nmol/L) during Dex treatment were elevated regardless of the newborn genital outcome. Maternal serum estriol (E3) levels in one mother (normal newborn genitalia) were consistently low (less than 0.2 nmol/L) during the second and third trimester. In two mothers (partially virilized newborn genitalia) initial second trimester E3 levels were unsuppressed (11, 17.4 nmol/L) and suppressed (less than 1.4 nmol/L) following short-term increased dose. CONCLUSION: prenatal Dex treatment of virilizing congenital adrenal hyperplasia at a dose of 1-1.5 mg daily throughout gestation is associated with significant maternal side effects. Parents should be informed of these side effects before initiation of treatment. Careful monitoring for signs of side effects, medical intervention when necessary, and lowering of Dex dose during the second half of gestation would minimize the side effects. Maternal serum E3 levels appear useful for prediction of fetal outcome while amniotic fluid steroid levels may not.

Coexistence of myelodysplastic syndrome and untreated chronic lymphocytic leukemia with development of acute myeloid leukemia immediately after treatment of chronic lymphocytic leukemia.

A 72-year-old man originally seen for anemia and thrombocytopenia was determined to have chronic lymphocytic leukemia (CLL). Bone marrow examination at the time of CLL diagnosis revealed a small but significant population of atypical blasts. Cytogenetic analysis of the bone marrow aspirate disclosed chromosomal abnormalities (-7, +8) suggestive of a myelodysplastic syndrome. Shortly after treatment of the CLL, there was proliferation of the previously noted blast population, which cytochemical studies demonstrated to be of the myeloid series thus indicating acute myeloid leukemia superimposed on CLL. This report presents microscopic, cytogenetic, immunophenotypic, and cytochemical evidence to document the evolution of acute myeloid leukemia in the bone marrow of a patient with CLL after one course of chemotherapy.

The Nager syndrome.

The Nager syndrome was identified in a newborn infant and in a subsequent sib by prenatal ultrasonography. This report documents an autosomal recessive pattern of inheritance for this disorder.

A cell hybrid and recombinant DNA library that facilitate identification of polymorphic loci in the vicinity of the Huntington disease gene.

Somatic cell hybrids were selected that retain a derivative chromosome 5 from an individual in which the p15.1-pter segment of chromosome 5 is replaced with the p15.1-pter segment of chromosome 4. Hybrids that retain this derivative chromosome exclusively were found to be positive for G8, a DNA marker closely linked to the Huntington disease gene on chromosome 4p. From one such hybrid, a segregant was isolated that had deleted the entire q arm of the derivative chromosome but retained the p arm intact as its only detectable human DNA. A complete recombinant DNA library was prepared from this cell line, and the inserts in approximately 1/3 of the recombinant phage with human DNA were shown to be derived from 4pter-4p15.1, which represents only approximately 1% of the total human genome. The cell hybrid and DNA library represent a rapid and efficient means to identify and isolate many polymorphic DNA markers close to and flanking the Huntington disease gene.

The steroid sulfatase locus on structurally abnormal inactive X chromosomes is expressed.

In mammalian somatic cells, sex-chromosome dosage compensation is achieved by random inactivation of one of the two X chromosomes. The Xg blood group antigen (Xg) and steroid sulfatase (STS) loci on the distal end of the short arm of the X chromosome have been shown to escape this inactivation. However, it has been reported that on structurally abnormal inactive X chromosomes Xg and STS are inactivated. This discrepancy requires further consideration since whatever process accounts for the lack of inactivation of these loci on structurally normal, inactive X chromosomes might be anticipated to be operative on structurally abnormal, inactive X chromosomes. To investigate this issue, we examined the expression of STS activity in mouse-human somatic-cell hybrids retaining two different, deleted, inactive human X chromosomes. These studies provide evidence for lack of inactivation of STS on structurally abnormal, inactive X chromosomes.

Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome.

Three unrelated stillborn infants (cases 1-3) are presented here with a distinct constellation of multiple anomalies: namely, multiple pterygia involving chin-to-sternum, cervical, axillary, antecubital, crural and/or popliteal areas, flexion contractures of multiple joints, small chest, hydrops, characteristic abnormal facial appearance with hypertelorism, markedly flattened nasal bridge with hypoplastic nasal alae, cleft palate, micrognathia, apparently low-set malformed ears, short neck with a cystic hygroma at the back of the neck and head, and pulmonary and cardiac hypoplasia. Radiographic studies, in addition, showed scalp edema, microbrachycephaly, flattened mandibular angle, lack of normal curvature at the cervico-thoracic junction, marked bony fusion of posterior spinous processes of older fetuses (cases 1, 2), thin crowded ribs, markedly hypoplastic scapulae, hypoplastic iliac wings, ischia and pubic bones, undermodeling of tubular bones, and radio-ulnar synostosis. Histologic studies of the skeletal system showed cartilaginous and bony fusion of the spinous processes (cases 1, 2), fusion of epiphyseal cartilages of distal humerus and proximal ulna, a poorly developed joint space, an abnormal growth plate, and weak safranin staining of the resting cartilages (cases 1, 2). To the best of our knowledge, this pattern of anomalies constitutes a previously undescribed syndrome. Prenatal diagnosis of this entity is possible by ultrasonographic studies on the basis of nonimmune fetal hydrops, a cystic hygroma at the back of the head and neck, diminished fetal activity, short and fixed limbs, and/or maternal hydramnios. Three additional cases (cases 4-6) are also presented to show a possible heterogeneity of this syndrome.

The Pena-Shokeir syndrome: report of five cases and further delineation of the syndrome.

We report on five cases of lethal Pena-Shokeir syndrome from three families with affected sibs. In addition to multiple anklyoses, camptodactyly, facial anomalies, and pulmonary hypoplasia, one fetus had pterygia of the neck and axillae and cardiac hypoplasia. Radiographic changes are nonspecific and probably are related to a lack of intrauterine movement. Our data and review of the literature suggest that pterygium formation is one of the manifestations of the Pena-Shokeir syndrome. A recently described lethal form of the recessively inherited multiple pterygium syndrome may represent a severe form of the Pena-Shokeir syndrome.

Site of action of 3',5'-cyclic adenosine monophosphate in production of tryptophanase in Escherichia coli.

3',5' cyclic-AMP (cAMP) will stimulate the rate of tryptophanase synthesis in Escherichia coli cultures induced with tryptophan. Adding cAMP after the initiation of messenger RNA synthesis was blocked by rifampicin, did not stimulate tryptophanase synthesis. This indicates that cAMP acts at initiation of either transcription or translation and not at the level of chain elongation of either the messenger or the polypeptide chain.