Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome.

Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild-type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2, encoding the B2 subunit of the multimeric vacuolar H(+) ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder.

New cases of Bohring-Opitz syndrome, update, and critical review of the literature.

We report on four additional unrelated cases of Bohring-Opitz syndrome with the highly characteristic phenotype of facial anomalies including bulging forehead over the metopic suture, frontal nevus flammeus, exophthalmos, hypertelorism, upslanting palpebral fissures, and cleft lip and/or palate, as well as flexion deformities of the upper limbs, multiple other anomalies, and severe failure to thrive. We also update the clinical outcome of the patients reported in the original article by Bohring et al. [Am J Med Genet 85:438-446] and critically review the subsequently published cases considered to have Bohring-Opitz syndrome.

Prospective, double-blind, randomized trial of equimolar mixture of nitrous oxide/oxygen to prevent pain induced by insertion of venous access ports in cancer patients.

BACKGROUND: To assess the efficacy of equimolar mixture of nitrous oxide/oxygen (EMNO) to prevent pain induced by venous access ports (VAPs) implantation in cancer patients. PATIENTS AND METHODS: In a randomized, double-blind study on an adult population not knowing the effects of EMNO, cancer patients were randomly assigned to breath via a facial mask, EMNO or a placebo mixture comprising 50% oxygen and 50% nitrogen. The primary end-point was the patients' assessment of the severity of pain evaluated using a visual analog scale (VAS, 0 to 100) and the proportion of patients suffering pain in each group. The secondary criteria were side effects, tolerability of EMNO, and the level of satisfaction of both the patients and the medical team. RESULTS: Eighty-three adults (42 in the EMNO group and 41 in the placebo group) were included. VAPs were implanted in the jugular vein in 95% of patients. In the placebo group, 78% of the patients declared that they found VAP implantation painful vs. 34% in the EMNO group (p=0.001). The severity of the pain was reduced by 50% in the EMNO group in comparison with placebo (p=0.0125). Although the median time to perform implantation was strictly identical in both groups (20 min), the estimated duration of surgery seemed longer to patients in the control group. Patient and investigator satisfaction indexes were >90% in both groups. CONCLUSION: EMNO provides an effective solution for the prevention of pain during placement of VAPs.

Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal syndrome (CFNS).

Craniofrontonasal syndrome (CFNS) is an X-linked disorder characterized by a more severe manifestation in heterozygous females than in hemizygous males. Heterozygous females have craniofrontonasal dysplasia (CFND) and occasionally extracranial manifestations including midline defects and skeletal abnormalities, whereas hemizygous males show no or only mild features such as hypertelorism and rarely show cleft lip or palate. Mutations in the EFNB1 gene in Xq12 are responsible for familial and sporadic CFNS. The EFNB1 gene encodes ephrin-B1, a transmembrane ligand that also exhibits receptor-like effects. We performed mutation analysis in nine unrelated families and 29 sporadic patients with CFNS. DNA sequencing revealed mutations in 33 (86.8%) cases including 26 distinct novel mutations. A recurrent nonsense mutation, c.196C>T/R66X, was detected in one family and four sporadic patients. The majority of mutations (26/33) were located in exons 2 and 3 of the EFNB1 gene encoding the extracellular ephrin domain. The mutation spectrum includes frameshift, nonsense, missense, and splice site mutations, with a predominance of frameshift and nonsense mutations resulting in premature truncation codons. For the first time we describe mutations in exons 4 and 5 of EFNB1. Of particular interest are the frameshift mutations located in the last 25 codons of EFNB1 encoding the carboxyterminal end of ephrin-B1. They result in an extension by 44 residues. These mutations disrupt the intracellular binding sites for Grb4 and PDZ-effector proteins involved in reverse signaling. We conclude that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor-ligand interaction, oligomerization, and ephrin-B1 reverse signaling.