Wilms tumor in patients with osteopathia striata with cranial sclerosis

Germline pathogenic variants in AMER1 cause osteopathia striata with cranial sclerosis (OSCS: OMIM 300373), an X-linked sclerosing bone disorder. Female heterozygotes exhibit metaphyseal striations in long bones, macrocephaly, cleft palate, and, occasionally, learning disability. Male hemizygotes typically manifest the condition as fetal or neonatal death. Somatically acquired variants in AMER1 are found in neoplastic tissue in 15–30% of patients with Wilms tumor; however, to date, only one individual with OSCS has been reported with a Wilms tumor. Here we present four cases of Wilms tumor in unrelated individuals with OSCS, including the single previously published case. We also report the first case of bilateral Wilms tumor in a patient with OSCS. Tumor tissue analysis showed no clear pattern of histological subtypes. In Beckwith–Wiedemann syndrome, which has a known predisposition to Wilms tumor development, clinical protocols have been developed for tumor surveillance. In the absence of further evidence, we propose a similar protocol for patients with OSCS to be instituted as an initial precautionary approach to tumor surveillance. Further evidence is needed to refine this protocol and to evaluate the possibility of development of other neoplasms later in life, in patients with OSCS.Subject terms: Genetics, Clinical genetics, Disease genetics     

Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord

ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.     

The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever

OBJECTIVE: The clinical profile in familial Mediterranean fever (FMF), including its major manifestation, amyloidosis, is influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. In this study, we analyzed the contribution of genotypes at the MEFV and SAA1 loci to disease severity and to the development of amyloidosis, and further defined the factors affecting the clinical profile of FMF. METHODS: We investigated a sample of 277 FMF patients (154 men and 123 women), including 62 patients with nephropathic amyloidosis, in whom both FMF alleles had been identified. A detailed chart review, interview, and physical examination were undertaken to determine the patients' demographic characteristics, medical history, clinical manifestations, and treatment. The disease severity score was calculated from the Tel-Hashomer key. Genotypes at the SAA1 locus (isoforms alpha, beta, and gamma) were determined in all patients. The SAA1 13C/T polymorphism of the SAA1 promotor was analyzed in a subset of cases. RESULTS: The male:female ratio (154:123, or 1.3) was higher among patients with amyloidosis (40:22, or 1.8) compared with patients without amyloidosis (114:101, or 1.1). Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio [OR] 4.27, 95% confidence interval [95% CI] 2.01-9.07), the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09), the occurrence of arthritis attacks (OR 2.43, 95% CI 1.17-5.06), and male sex (OR 1.73, 95% CI 0.90-3.33) were significantly and independently associated with renal amyloidosis. Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus. The SAA1 13T allele was rare, being associated mainly with the SAA gamma isoform, and not related to renal amyloidosis. CONCLUSION: Overall, disease severity and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene.     

A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.     

Duplication of 20p12.3 associated with familial Wolff–Parkinson–White syndrome

Wolff–Parkinson–White (WPW) syndrome is caused by preexcitation of the ventricular myocardium via an accessory pathway which increases the risk for paroxysmal supraventricular tachycardia. The condition is often sporadic and of unknown etiology in the majority of cases. Autosomal dominant inheritance and association with congenital heart defects or ventricular hypertrophy were described. Microdeletions of 20p12.3 have been associated with WPW syndrome with either cognitive dysfunction or Alagille syndrome. Here, we describe the association of 20p12.3 duplication with WPW syndrome in a patient who presented with non‐immune hydrops. Her paternal uncle carries the duplication and has attention‐deficit hyperactivity disorder and electrocardiographic findings consistent with WPW. The 769 kb duplication was detected by the Affymetrix Whole Genome‐Human SNP Array 6.0 and encompasses two genes and the first two exons of a third gene. We discuss the potential role of the genes in the duplicated region in the pathogenesis of WPW and possible neurobehavioral abnormalities. Our data provide additional support for a significant role of 20p12.3 chromosomal rearrangements in the etiology of WPW syndrome. © 2012 Wiley Periodicals, Inc.     

Multiple ganglion cysts ('cystic ganglionosis'): an unusual presentation in a child

A case of multifocal and recurrent ganglion cysts is described. An 11-year-old boy was referred because of symptomatic cystic masses in the extremities since the age of 2 years. Over the years, he had experienced intermittent appearance of these lesions, which were associated with pain, but without any systemic manifestations. Magnetic resonance imaging (MRI) showed cystic lesions with synovio-capsular thickening along the temporomandibular joints (TMJ), atlanto-axial synovial articulation, and tendons and joints of the right wrist and hand. Histopathological examination of one lesion showed anastomosing fibro-connective tissue surrounded by a wall of smooth muscle and fibrous connective tissue, findings that were consistent with ganglion cyst. The early onset of the disease, as well as the involvement of multiple and unusual sites, including the TMJ, implies a genetic susceptibility to these lesions that we refer to as 'cystic ganglionosis'.     

15q13q14 deletions: phenotypic characterization and molecular delineation by comparative genomic hybridization

We report on a detailed phenotypic characterization of two patients with novel de novo deletions involving 15q13q14, a chromosomal region immediately distal to the Prader-Willi/Angelman syndrome critical interval. Both cases were detected by the clinical array-based comparative genomic hybridization (array-CGH) and were precisely delineated through the high-density Agilent 244 K oligonucleotide array. The comparison of our patients with previously reported deletion cases involving the 15q13q14 region demonstrated a recurrent pattern of developmental anomalies including mild dysmorphic features, cleft palate/bifid uvula, congenital heart defects (PFO or ASD), developmental delay, and learning disabilities. The potential role of the genes within the deleted region in the pathogenesis of these various phenotypic abnormalities is discussed.