Aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD) are the characteristic findings of Adams–Oliver syndrome (AOS). The variable clinical spectrum further includes ...cardiac, neurologic, renal, and ophthalmological findings. Associated genes in AOS are in the Notch and the CDC42/Rac1 signaling pathways. Both autosomal‐dominant and autosomal‐recessive inheritances have been reported, the latter with pathogenic variants in DOCK6 or EOGT. The EOGT‐associated recessive type of AOS has been postulated to present a more favorable prognosis. We here report a 12‐year‐old girl from a refugee family of Iraq with consanguineous parents. She was born with a severe phenotype of AOS presenting a large ACC of the scalp with an underlying skull defect, which was often infected and inflamed. Afterward, additional ulceration developed. Furthermore, the girl showed microcephaly, TTLD on both hands and feet, and neurological findings: spastic paresis, epilepsy and suspicion of intellectual deficit. Molecular genetic analysis (next‐generation sequencing) revealed a novel frameshift mutation in the EOGT gene in Exon 13 in homozygous constellation: c.1013dupA p.(Asn338Lysfs*24). A biopsy within an ulceration at the scalp ACC showed a cutaneous squamous cell carcinoma (cSCC) with local invasive growth into the dura, the meninges, and the cortex. Treatment including surgical resection and focal irradiation was not curative and the girl deceased 6 months after initial diagnosis. This report on a patient with AOS and an autosomal‐recessive EOGT gene variant dying of a local aggressive cSCC at an ACC lesion shows that close monitoring of ACC is essential.
Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in ...many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage.
Nail-Patella syndrome (MIM 161200) is a rare autosomal dominant disorder characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows, and iliac horn. In 40% of cases, a ...glomerular defect is present and, less frequently, ocular damage is observed. Inter- and intrafamilial variable expressivity of the clinical phenotype is a common finding. Mutations in the human LMX1B gene have been demonstrated to be responsible for Nail-Patella syndrome in around 80% of cases.
Standard polymerase chain reaction and sequencing methods were used for mutation and single nucleotide polymorphism identification and control of cloned sequences. Array-CGH (Agilent, 244A Kit) was used for detection of deletions. Standard cloning techniques and the Snapshot method were used for analysis of mosaicism.
In this study, we present the results of LMX1B screening of 20 Nail-Patella syndrome patients. The molecular defect was found in 17 patients. We report five novel mutations and a ∼2 Mb deletion in chromosome 9q encompassing the entire LMX1B gene in a patient with a complex phenotype. We present evidence of somatic mosaicism in unaffected parents in two cases, which, to our knowledge, are the first reported cases of inheritance of a mutated LMX1B allele in Nail-Patella syndrome patients from a mosaic parent.
The study of the described case series provides some original observations in an “old” genetic disorder.
BACKGROUNDMoebius syndrome is a rare disorder with minimum clinical criteria of congenital facial weakness in association with impairment in abduction of one or both eyes. Mirror movements are not ...known to be associated with Moebius syndrome. CASE REPORTWe present three patients who meet minimum criteria for a diagnosis of Moebius syndrome and who also display mirror movements. DISCUSSIONThis case series suggests that Moebius syndrome may be associated with mirror movements. Further investigation to delineate the genetic etiologies of Moebius syndrome is ongoing. Patients with Moebius syndrome and mirror movements may represent a specific subclass of this disorder.
Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases ...the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition.
With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed.
In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation.
This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.
The disconnected (disco)‐interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase‐associated protein 1 (DMAP1) binding domain, Acyl‐CoA ...synthetase domain and AMP‐binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco‐interacting protein 2 homolog A (DIP2A), Disco‐interacting protein 2 homolog B (DIP2B), and Disco‐interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss‐of‐function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss‐of‐function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10–24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss‐of‐function variants in DIP2C with a neurocognitive phenotype.
Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have ...identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1−/− mouse phenotype. The missense variant is predicted to result in the substitution of a cysteine for an arginine at amino acid residue 207 (Arg207Cys), which corresponds to the highly conserved Arg5 of the homeodomain. Arg5 interacts with thymine in the minor groove of DNA through hydrogen bonding and electrostatic attraction. Molecular modeling and an in vitro DNA-protein binding assay predict that the mutation would disrupt these interactions, destabilize the HOXB1:PBX1:DNA complex, and alter HOXB1 transcriptional activity.
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