Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region

Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.     

Allergies in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) and patients with chronic granulomatous disease

Humoral immunodeficiencies have a recognized association with atopy. This study investigated the association of a T-cell disorder (chromosome 22q11.2 deletion) and a neutrophil disorder [chronic granulomatous disease (CGD)] with asthma, eczema, and rhinitis using a standardized survey instrument. Patients were recruited from either a national referral center (chromosome 22q11.2 deletion syndrome) or from a registry (CGD). Controls consisted of siblings of patients. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) was found to be significantly associated with both eczema and asthma but not allergic rhinitis. CGD was not found to be significantly associated with atopic diseases.     

Basilar venous plexus of the posterior fossa: a potential source of error in petrosal sinus sampling

Sampling of serum from the inferior petrosal sinus can provide important information about the source of elevated adrenocorticotropic hormone (ACTH) levels. This often leads to improved results of pituitary surgery for Cushing disease. The authors describe a successful catheterization technique and illustrate the venous anatomy of the inferior petrosal sinuses and basilar plexus.     

Analysis of clinical variation seen in patients with 18q terminal deletions

Twenty-six patients with deletions of 18q were analyzed at the clinical and molecular levels in an attempt to delineate regions of chromosome 18 important to the 18q– syndrome phenotype. Molecular cytogenetic analysis was carried out using fluorescence in situ hybridization (FISH), and deletions ranging from 18q21.1–qter to 18q22.3–qter were detected. The parental origin of the deletions was determined by the analysis of inheritance of microsatellite markers. No correlation between size, parental origin, or severity of the resulting phenotype was found. The results suggest that a critical region for the 18q– syndrome lies in the most distal portion of 18q and that it confers susceptibility for the various clinical manifestations of the 18q– syndrome when present in one copy. © 1995 Wiley-Liss, Inc.     

Site-specific reciprocal translocation,t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction

We have studied 32 unrelated families with a site-specific reciprocal translocation between chromosomes 11 and 22 [t(11;22) (q23;q11)]. In translocation heterozygotes 3:1 meiotic segregation occurs and results in abnormal progeny who carry the der(22) as a supernumerary chromosome. Phenotypic findings consistent with 47,XX (or XY), +der(22), t(11;22) include mental retardation, preauricular skin tag and/or sinus, ear anomaly, palate anomaly, micrognathia, congenital heart disease, and genital anomalies in males. The frequency of abortions among offspring of male and female heterozygotes is increased. Segregation analysis shows that the risk for unbalanced offspring to be born to female heterozygotes may be as high as 10%, and that there may be a significant risk to male heterozygotes as well. The overall carrier frequency among progeny of 11;22 translocation carriers is 70.6%. The occurrence of multiple 11;22 translocation events is supported by de novo occurrence of the translocation, familial heteromorphic variants of the der(22), and varied racial and ethnic backgrounds of the families. To our knowledge, with the exclusion of centric fusion translocations, this represents the only example of nonrandom exchange in a constitutional chromosomal rearrangement.