Constitutional 560.49 kb chromosome 2p24.3 duplication including the MYCN gene identified by SNP chromosome microarray analysis in a child with multiple congenital anomalies and bilateral Wilms tumor.

Fewer than 100 patients with partial chromosome 2p trisomy have been reported. Clinical features are variable and depend on the size of the duplicated segment, but generally include psychomotor delay, facial anomalies, congenital heart defect, and other abnormalities. We report a 560.49 kb duplication of chromosome 2p in a 13 month-old male with hydrocephaly, ventricular septal defect, partial agenesis of the corpus callosum, and bilateral Wilms tumor. After discovery of bilateral renal masses at four months of age, the child underwent neoadjuvant chemotherapy followed by right radical nephrectomy that revealed triphasic Wilms' tumor. A needle core biopsy on one of two lesions on the left kidney also revealed Wilms tumor. A partial left nephrectomy revealed focally positive margins that necessitated left flank radiotherapy. The tumor karyotype was 46,XY,t(7;8)(q36;p11)[8]/46,XY [12] while his constitutional karyotype was 46,XY, suggesting that the t(7;8)(q36;p11) was associated with the malignancy. Single nucleotide polymorphism (SNP) chromosome microarray analysis of peripheral blood identified a maternally-inherited 560.49 kb chromosome 2p24.3 duplication that involved four OMIM genes: NBAS, DDX1, MYCNOS, and MYCN. SNP array analysis of the tumor revealed the same 2p24.3 duplication. At present, the now 5-year-old boy continues to do well without clinical or radiographic evidence of recurrent disease. This case is instructive because the child's health insurer initially denied authorization for chromosome microarray analysis (CMA), and it took more than one year before such authorization was finally granted. That initial decision to deny coverage could have had untoward health implications for this child, as the identification of constitutional MYCN duplication necessitated surveillance imaging for a number of pediatric malignancies associated with MYCN overexpression/dysregulation.

Velopharyngeal insufficiency, submucous cleft palate and a phonological disorder as the associated clinical features which led to the diagnosis of Jacobsen syndrome. Case report and review of the literature.

Jacobsen syndrome is an uncommon but well-known contiguous gene syndrome caused by partial deletion involving the long arm of chromosome 11. Most common features include: psychomotor impairment, facial dysmorphism, and thrombocytopenia. Cleft palate has been rarely reported. A case of Jacobsen syndrome confirmed by cytogenomic analysis is presented with review of the literature. Main clinical features were phonological disorder, submucous cleft palate (SMCP) and velopharyngeal insufficiency (VPI). VPI was corrected surgically according to findings of videonasopharyngoscopy and videofluoroscopy. It is concluded that clinicians should consider that VPI associated with SMCP may be the main manifestations of a chromosomal syndrome.

Pseudohypoparathyroidism type 1A and morbid obesity in infancy.

OBJECTIVE: To describe an infant with early excessive weight gain as the principle manifestation of pseudohypoparathyroidism (PHP) type 1a and Albright hereditary osteodystrophy (AHO). METHODS: We describe the clinical and laboratory findings in an infant with early excessive weight gain without evidence of hyperphagia and review relevant literature. RESULTS: The proband's birth weight was 4047 g (1.4 SD). She was breastfed from birth. Excessive weight gain was noted by 1 month of age. At 3 months of age, hard subcutaneous nodules were observed, and histologic analysis of a biopsied lesion suggested a possible diagnosis of ossified pilomatricoma. At 6 months of age, she was documented to have mild hypothyroidism. Abnormal weight gain continued despite a caloric intake of about 65 kcal/kg per day. At 11 months of age, 2 new subcutaneous hard nodules were identified, which in the context of excessive weight gain and evolving mild primary hypothyroidism, suggested a unifying diagnosis of PHP type 1a and AHO. GNAS sequence analysis was performed, which revealed a 4-base deletion (Nt565delGACT) in exon 8. CONCLUSIONS: As more monogenic causes of severe early obesity are described, it is important to consider PHP type 1a in the differential diagnosis. Lack of short stature, skeletal abnormalities, or absence of PTH resistance should not exclude this diagnosis in a young child.

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Further delineation of Kabuki syndrome in 48 well-defined new individuals.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

Detection of deletions in de novo "balanced" chromosome rearrangements: further evidence for their role in phenotypic abnormalities.

PURPOSE: The purpose of this study was to test the hypothesis that deletions of varying sizes in de novo apparently balanced chromosome rearrangements are a significant cause of phenotypic abnormalities. METHODS: A total of fifteen patients, with seemingly balanced de novo rearrangements by routine cytogenetic analysis but with phenotypic anomalies, were systematically analyzed. We characterized the breakpoints in these fifteen cases (two of which were ascertained prenatally), using a combination of high-resolution GTG-banding, fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes (BACs), and data from the Human Genome Project. RESULTS: Molecular cytogenetic characterization of the 15 patients revealed nine with deletions, ranging in size from 0.8 to 15.3 Mb, with the number of genes lost ranging from 15 to 70. In five of the other six cases, a known or putative gene(s) was potentially disrupted as a result of the chromosomal rearrangement. In the remaining case, no deletions were detected, and no known genes were apparently disrupted. CONCLUSIONS: Our study suggests that the use of molecular cytogenetic techniques is a highly effective way of systematically delineating chromosomal breakpoints, and that the presence of deletions of varying size is an important cause of phenotypic abnormalities in patients with "balanced" de novo rearrangements.

Delineation of complex chromosomal rearrangements: evidence for increased complexity.

There is an assumption of parsimony with regard to the number of chromosomes involved in rearrangements and to the number of breaks within those chromosomes. Highly complex chromosome rearrangements are thought to be relatively rare, with the risk for phenotypic abnormalities increasing as the number of chromosomes and chromosomal breaks involved in the rearrangement increases. We report here five cases of de novo complex chromosome rearrangements, each with a minimum of four breaks. Deletions were found in four cases, and in at least one case, a number of genes or potential genes might have been disrupted. This study highlights the importance of the detailed delineation of complex rearrangements, beginning with high-resolution chromosome analysis, and emphasizes the utility of fluorescence in situ hybridization in combination with the data available from the Human Genome Project as a means to delineate such rearrangements.

Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children.

The differential diagnosis of developmental delays and growth retardation in early childhood includes the allelic lysosomal sialic acid storage disorders, Salla disease and infantile free sialic acid storage disease (ISSD). These diseases, due to defective free sialic acid transport out of lysosomes, derive from mutations in the SLC17A5 gene coding for the protein sialin. We present two patients with clinical, biochemical, and molecular data indicative of lysosomal free sialic acid storage disorders. One patient, with a severe clinical course typical of ISSD, had 86-fold elevated levels of fibroblast free sialic acid, with 62% in the lysosomal fraction. His SLC17A5 mutations include a 148-bp deletion of exon 9, due to a G >A splice site mutation in position 1 of intron 9, and a 15-bp deletion (del 801-815) in exon 6. Another patient, with "intermediate severe" Salla disease, had 9-fold elevated levels of free sialic acid in cultured fibroblasts, of which 87% resided in the lysosomal fraction. This girl is compound heterozygous for the SLC17A5 mutation commonly found in Finnish Salla disease patients (R39C) and a 15-bp deletion found in ISSD patients (del 801-815). These observations emphasize the importance of considering free sialic acid disorders in infants with developmental delays and growth retardation, regardless of whether they are of Finnish ancestry.

X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male.

X-linked dominant chondrodysplasia punctata (CDPX2; Happle syndrome) is recognized almost exclusively in females, who display mosaic and asymmetric features, presumed to arise secondary to random X-inactivation. CDPX2 results from mutation of an X-linked gene coding for sterol-delta(8)-delta(7) isomerase (emopamil binding protein). We describe a boy with clinical features of CDPX2 (including those presumed to arise usually secondary to functional mosaicism in females). Biochemical and molecular studies demonstrate that he is mosaic for a sterol-delta(8)-delta(7) isomerase gene mutation. He is the first reported example of single gene mosaicism giving rise to CDPX2 in a male.

Cerebro-osseous-digital syndrome: four new cases of a lethal skeletal dysplasia--distinct from Neu-Laxova Syndrome.

Neu-Laxova Syndrome (NLS) is a severe disorder with intrauterine growth retardation, edema, and characteristic face (including microcephaly with receding forehead, protuberant eyes, a flattened nose, deformed ears, cleft palate, and micrognathia). Ichthyosis is often present. Limb anomalies include hypoplastic fingers and syndactyly of fingers and toes. Patients are usually stillborn or die shortly after birth. We report five unrelated patients--four with atypical NLS and one with typical NLS. All five patients were stillbirths. Clinically, the atypical NLS patients showed a large skull; rhizo-, meso-, and acromelia; and hypoplasia of the metacarpals and phalanges. The feet were similarly affected. Radiographically, the atypical patients showed interpediculate narrowing and hypoplastic vertebral bodies. The long bones were stick-like, showing diaphyseal widening that spared the metaphyses and was more pronounced in the lower extremities. The ilia had a half-moon configuration with widening of the sacrosciatic notches. The ischia were vertical and the pubic bone was absent. The typical NLS patient showed microcephaly, normal vertebral body, and long bone ossification, but a pelvic configuration similar to that of the atypical NLS patients. The common and distinguishing clinical and radiographic features are reviewed. Scott et al. [1981: Am J Med Genet 9:165-175] described two patients with NLS with radiographic and clinical findings similar to patients 1-4 reported here. Patients 1-4 of this report lack the typical findings of NLS and likely represent a distinct lethal skeletal dysplasia.