Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects.

Inherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length.

Obstrucción colónica por pólipo hamartomatoso en una paciente pediátrica con esclerosis tuberosa / Bowel obstruction by hamartomatous polyp in a pediatric patient with tuberous sclerosis

La esclerosis tuberosa es una enfermedad autosómica dominante con gran variabilidad de expresión clínica. Se caracteriza por la presencia de tumores benignos en distintos órganos debidos a un desorden en la proliferación y diferenciación celular. Afecta, especialmente, la piel, el sistema nervioso central, el corazón y el riñón. El compromiso intestinal es infrecuente; afecta a adultos y compromete el colon sigmoide y el recto. En niños, hay solo dos casos descritos en la literatura; nuestra paciente sería el tercero. Presentamos a una paciente con esclerosis tuberosa, que comenzó, desde el mes de vida, con cuadros reiterados de suboclusión intestinal. La videocolonoscopía mostró una formación mamelonada que protruía hacia la luz del colon ascendente. Se realizó una hemicolectomía derecha. El informe anatomopatológico correspondió a un pólipo hamartomatoso. La evolución clínica y nutricional en el posquirúrgico fue muy favorable. Aunque poco frecuente, el pólipo hamartomatoso debe considerarse en el diagnóstico diferencial de oclusión intestinal en pediatría.

Tuberous sclerosis is an autosomal dominant disorder with a wide clinical spectrum of disease. It is characterized by development of benign tumors in multiple organs due to a disturbance in cellular growth and differentiation. It usually affects skin, brain, heart and kidney. Gastrointestinal involvement is rare and mainly restricted to adults and sigmoid colon and rectum. In children there are only two cases; our patient would be the third. We present a patient with tuberous sclerosis who began at the first month of life with repeated intestinal subocclusion. The videocolonoscopy showed a mass protruding into the lumen of the ascending colon. Right hemicolectomy was performed. The anatomopathological report corresponded to a hamartomatous polyp. The clinical and nutritional evolution in the postoperative period was very favorable. Although uncommon, the hamartomatous polyp should be considered in the differential diagnosis of intestinal occlusion in pediatrics.

[Bowel obstruction by hamartomatous polyp in a pediatric patient with tuberous sclerosis]. / Obstrucción colónica por pólipo hamartomatoso en una paciente pediátrica con esclerosis tuberosa.

Tuberous sclerosis is an autosomal dominant disorder with a wide clinical spectrum of disease. It is characterized by development of benign tumors in multiple organs due to a disturbance in cellular growth and differentiation. It usually affects skin, brain, heart and kidney. Gastrointestinal involvement is rare and mainly restricted to adults and sigmoid colon and rectum. In children there are only two cases; our patient would be the third. We present a patient with tuberous sclerosis who began at the first month of life with repeated intestinal subocclusion. The videocolonoscopy showed a mass protruding into the lumen of the ascending colon. Right hemicolectomy was performed. The anatomopathological report corresponded to a hamartomatous polyp. The clinical and nutritional evolution in the postoperative period was very favorable. Although uncommon, the hamartomatous polyp should be considered in the differential diagnosis of intestinal occlusion in pediatrics.

La esclerosis tuberosa es una enfermedad autosómica dominante con gran variabilidad de expresión clínica. Se caracteriza por la presencia de tumores benignos en distintos órganos debidos a un desorden en la proliferación y diferenciación celular. Afecta, especialmente, la piel, el sistema nervioso central, el corazón y el riñón. El compromiso intestinal es infrecuente; afecta a adultos y compromete el colon sigmoide y el recto. En niños, hay solo dos casos descritos en la literatura; nuestra paciente sería el tercero. Presentamos a una paciente con esclerosis tuberosa, que comenzó, desde el mes de vida, con cuadros reiterados de suboclusión intestinal. La videocolonoscopía mostró una formación mamelonada que protruía hacia la luz del colon ascendente. Se realizó una hemicolectomía derecha. El informe anatomopatológico correspondió a un pólipo hamartomatoso. La evolución clínica y nutricional en el posquirúrgico fue muy favorable. Aunque poco frecuente, el pólipo hamartomatoso debe considerarse en el diagnóstico diferencial de oclusión intestinal en pediatría.

[Diagnosis and treatment of gastrointestinal bleeding in Bean syndrome]. / Diagnóstico y tratamiento de hemorragia digestiva en síndrome de Bean (Blue Rubber-Bleb Nevus Syndrome).

Blue Rubber-Bleb Nevus Syndrome (BRBNS, Bean Syndrome) is a rare disorder characterized by the presence of cutaneous and visceral vascular malformations. Although it may affect several organs, the gastrointestinal tract is one of the most frequently involved sites. It can cause gastrointestinal bleeding and chronic anemia. We report an 8-years-old girl who was admitted because of cutaneous malformations and anemia suspected to be caused by gastrointestinal bleeding. Cutaneous lesions were compatible with Blue Rubber-Bleb Nevus Syndrome. Vascular malformations were confirmed by diagnostic gastroduodenoscopy and colonoscopy and further therapeutical intervention was planned. We performed banding of 2 lesions located in the stomach and sclerotherapy of a duodenal lesion. Six colonic lesions were treated with banding and three other polypoid lesions were endoscopically resected A combined laparoscopic and endoscopic approach was performed for evaluation and treatment of small-bowel lesions. Eighteen lesions were found. We endoscopically resected 8 polipoid lesions. Eight other large transmural lesions were removed by wedge resection. Only one lesion required termino-terminal anastomosis. We consider that endoscopic treatment and laparoscopically assisted enteroscopy are safe and effective options in the treatment of gastrointestinal bleeding caused by vascular malformations.