WAGR(O?) syndrome and congenital ptosis caused by an unbalanced t(11;15)(p13;p11.2)dn demonstrating a 7 megabase deletion by FISH.

Aniridia usually occurs in isolation, but may also occur as part of the WAGR contiguous gene deletion syndrome, which includes Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. The aniridia and predisposition for Wilms tumor seen in WAGR are caused by haploinsufficiency for PAX 6 and WT1, respectively. We present a female infant with aniridia, bilateral ptosis, bilateral posterior capsular cataracts, nystagmus, left-sided glaucoma, microcephaly, mild unilateral hydronephrosis, poor linear growth, and gross motor delay consistent with a clinical diagnosis of WAGR syndrome. In addition, weight-for-height ratio at 12 months is at the 94th centile, raising the possibility of a diagnosis of WAGRO (WAGR + Obesity). Chromosome analysis revealed a translocation (11;15)(p13;p11.2) which has not been previously associated with a diagnosis of WAGR. Subsequent clinical WAGR fluorescent in situ hybridization (FISH) analysis demonstrated a deletion of 11p13 including PAX6 and WT1. A complete FISH-mapping of the breakpoints on chromosome 11 revealed a 7 Mb deletion within 11p13-11p14. The patient is examined in light of other reported patients with deletions and/or translocations involving the regions between 11p12 --> 11p14 including patients with WAGR + obesity (WAGRO) as well as with other reported patients with aniridia and congenital ptosis.

Filippi syndrome: report of three additional cases.

Filippi syndrome is an autosomal recessive condition characterized by variable soft tissue syndactyly of the fingers and toes, microcephaly, pre- and postnatal growth retardation, mildly abnormal craniofacial appearance, and mental retardation. We report on three unrelated individuals with Filippi syndrome. All have microcephaly, minor facial anomalies, variable syndactyly of digits, growth impairment, and developmental delay. One patient also has polydactyly, which has not been reported previously in the Filippi syndrome.

Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome.

Renal-Coloboma syndrome, an autosomal dominant disorder characterized by colobomatous eye defects, vesicoureteral reflux, and abnormal kidneys, results from mutations in PAX2. The purpose of this study was to identify mutations in PAX2 and understand the associated patient phenotypes. We report a severely affected girl and a mildly affected mother and daughter, all of whom have PAX2 homoguanine tract (7 G) missense mutations. The mother and daughter have optic nerve colobomas and the daughter has vesicoureteral reflux. The severely affected girl developed renal failure and has bilateral colobomatous eye defects. Additionally, this girl developed hydrocephalus associated with platybasia and a Chiari 1 malformation. We examined genomic DNA from these individuals by SSCP and sequencing. The mother and daughter had a novel mutation: a contraction in a string of 7 G's to 6 G's in one allele of PAX2, leading to a premature stop codon two amino acids downstream. The severely affected girl had an expansion to 8 G's, leading to a premature stop codon 27 amino acids downstream. The 8 G expansion has been found in other patients without brain anomalies and has occurred spontaneously in a mouse model, PAX2(1Neu). We expand the known phenotype associated with mutations in PAX2 to include brain malformations. The homoguanine tract in PAX2 is a hot spot for spontaneous expansion or contraction mutations and demonstrates the importance of homonucleotide tract mutations in human malformation syndromes.

Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Renal tubular dysgenesis, absent nipples, and multiple malformations in three brothers: a new, lethal syndrome.

We report on three brothers with renal tubular dysgenesis and absent nipples, each also had other malformations including pre-auricular pits and a preauricular tag, branchial clefts, choanal atresia, pulmonary lobation anomaly, ventricular septal defect, type IIB interrupted aortic arch, absent gallbladder, absent thymus, parathyroid gland, accessory spleen, imperforate anus, clinodactyly, and broad digits and small nails. All three infants died neonatally. This pattern of clinical malformations appears to be a previously unreported syndrome.

Marden-Walker syndrome: a case report and a critical review of the literature.

We present a patient with blepharophimosis, joint contractures, immobile facies, decreased muscular bulk, postnatal growth retardation, developmental delay, micrognathia, cleft palate, camptodactyly, arachnodactyly, pectus, kyphoscoliosis, hypospadias, and absent deep tendon reflexes. These findings are consistent with Marden-Walker syndrome (MWS). Twenty-two additional cases in the literature are reviewed. Diagnostic criteria are proposed, and the spectrum of variability is discussed. Evidence for autosomal recessive inheritance is reviewed as is the differential diagnosis. Possible pathogenetic mechanisms are considered.

Lethal congenital muscular dystrophy with cataracts and a minor brain anomaly: new entity or variant of Walker-Warburg syndrome?

A term newborn male with severe hypotonia and contractures was found to have dense bilateral cataracts. He died at age 3 days of respiratory failure. Amino acidopathies and disorders of peroxisome function were excluded, and results of serologic studies and placental histopathology, specifically seeking evidence of intrauterine infection, were normal. Autopsy showed changes in the skeletal muscles consistent with congenital muscular dystrophy and a small focal anomaly of the cerebral cortex. These findings either represent a new syndrome or raise further questions about broadening the spectrum of known congenital muscular dystrophy syndromes with associated eye and brain anomalies.

Congenital heart disease and Robinow syndrome: coincidence or an additional component of the syndrome?

We report on a girl with Robinow syndrome and pulmonary atresia with ventricular septal defect (VSD). Seven cases of Robinow syndrome with congenital heart defect (CHD) have now been described, 5 of whom had stenosis or atresia of the pulmonic valve. This suggests that CHD, especially right ventricular outlow obstruction, may be a component manifestation of this syndrome in some cases. Since early recognition of this type of heart lesion can minimize morbidity by facilitating optimal surgical therapy, thorough cardiac evaluation of all patients with Robinow syndrome seems warranted.