Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

Pyoderma gangrenosum associated with pseudo-Pelger-Huet anomaly in a patient with idiopathic myelofibrosis.

Pseudo-Pelger-Huët anomaly is a condition in which almost all the granulocytes are hyposegmented and/or hypogranulated. It is typically recognized in peripheral blood smears and represents a marker of several disorders, such as myeloproliferative diseases and myelodysplasia. The occurrence of the pseudo-Pelger-Huët anomaly in the cutaneous infiltrate of pyoderma gangrenosum is very rare. We describe the case of a 70-year-old man with idiopathic myelofibrosis who developed pyoderma gangrenosum. Histological examination showed an infiltrate consisting of granulocytic elements with features of dysmaturity and segmentation anomalies (hypo- and hypersegmented forms), suggestive of pseudo-Pelger-Huët anomaly. Methylprednisolone treatment resulted in progressive improvement of pyoderma gangrenosum.

Severe SOPH syndrome due to a novel NBAS mutation in a 27-year-old woman-Review of this pleiotropic, autosomal recessive disorder: Mystery solved after two decades.

Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Hüet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Hüet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.

Chronic myelogenous leukaemia with a p53 mutation demonstrated neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly) and hypogranulation in the peripheral blood smear.

A 70-year-old man visited our emergency department, whose laboratory test results revealed leucocytosis, anaemia, thrombocytopenia and high levels of serum lactate dehydrogenase. In addition, the peripheral blood smear revealed neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly), hypogranulation and no myeloperoxidase reactivity. Genetic testing of the peripheral blood sample was as follows: G-band, 46XY,t(9;22)(q34;q11.2) (20/20); fluorescence in situ hybridisation BCR/ABL fusion signal, 97%; and analysis of exons 5-9 of the p53 gene, mutation (Pro72Arg) in exon 4 protein. On the basis of these findings, the patient was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase with a p53 mutation and treated with hydroxyurea, dasatinib and nilotinib. Neutrophilic granulocytes with the anomalies were no longer observed after achieving cytogenetic remission. To the best of our knowledge, this is the first report of CML case with the anomalies, in which a p53 mutation without chromosome 17 abnormalities was identified.

[Short stature, optic nerve atrophy and Pelger-Huët anomaly syndrome with antibody immunodeficiency and aplastic anemia: a case report and literature review].

Objective: To investigate the clinical features and genetic characteristics of cases with NBAS gene defects. Method: Characteristics of clinical materials, immunological data and gene mutation of the first case in China with NBAS gene mutation were retrospectively analyzed. The related literature was searched by using search terms'NBAS'. Result: A 2-year-four-month old girl, was admitted due to 'fever and pallor for one day'. There was an intrauterine growth retardation at her fetal stage. Since her birth, she had suffered from recurrent infections and development delay was accompanied by persistent liver dysfunction. Her head circumference and height were 43.5 cm and 60 cm, respectively. She seemed pale. She had progeroid appearance with loose skin, sparse hair, proptosis and low-set ears. The cranial suture did no close and the anterior fontanel was about 6 cm×5 cm. Abdominal palpation showed that the liver was 2 cm below the right costal margin, and the spleen was 1.5 cm below the left rib. Both alanine aminotransferase(100-1 991 IU/L) and aspartate aminotransferase (191-1 367 IU/L) were persistently abnormal. Visual evoked potentials and fundus examination revealed optic nerve atrophy. Bone mineral density assessment showed osteoporosis. The IgG level was 2.0 g/L (3.41-19.6) and absolute count of CD19(+)B cells was 231.27/µl (608.8-2 167.7) . Her hemoglobin level was 53 g/L. Bone marrow smear showed serious hypoplasia in erythroid cell. The gene sequencing results showed NBAS gene c.5741C> T, pR1914H and c.6496-6497insA, p.S2166Ffs* 2 compound heterozygous mutations. A total of 8 literatures were collected including 57 cases with NBAS gene homozygous or compound heterozygous mutation. These 57 cases were characterized by short stature(88%, 50/57) , Pelger-Huët anomaly (75%, 43/57) , skeletal dysplasia (74%, 42/57), optic nerve atrophy (72%, 41/57), abnormality of liver enzymes or acute liver failure (42%,24/57), abnormalities of immune system(19%, 11/57), development delay of mental, language or sports(11%, 6/57). Other clinical manifestations such as progeroid appearance, proptosis and hypotonia were also common. NBAS gene c.5741G>A homozygous mutation accounted for 61% (35/57) cases. Conclusion: Cases with NBAS gene defects often manifests as short stature, optic nerve atrophy, Pelger-Huët anomaly, skeletal dysplasia, recurrent infections, abnormality of liver enzymes, progeroid appearance, proptosis, hypotonia and immunodeficiency. Gene sequencing analysis showed NBAS gene homozygous or compound heterozygous mutations, and homozygous mutation of c.5741G>A was most common.

Transient Deformation of Neutrophils in Kawasaki Disease.

In the treatment of Kawasaki disease, resistance to high-dose immunoglobulin intravenous (IGIV) can occur. The neutrophil morphology analyses in 17 patients revealed that transient pseudo-Pelger-Huët anomaly was more frequently detected in the IGIV-resistant group. This finding may aid the prediction of IGIV resistance.

Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly.

BACKGROUND: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. AIMS: To identify a causative gene for SOPH syndrome. METHODS: Genomewide homozygosity mapping was conducted in 33 patients in 30 families. RESULTS: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. CONCLUSION: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.

The pseudo-Pelger-Huët anomaly in pyoderma gangrenosum associated with myelodysplastic syndrome.

We report a case of pyoderma gangrenosum in which most of the neutrophils exhibited the pseudo-Pelger-Huët (pPH) anomaly, a cytologic abnormality affecting the neutrophil nucleus. Pelgeroid cells have round, oval, or hyposegmented nuclei and are therefore difficult to recognize as neutrophils. The pPH anomaly is important because it is found mostly in patients with myelodysplastic syndromes or myeloid leukemias. These patients are also at risk for developing neutrophilic dermatosis as well as leukemia cutis, the main differential diagnosis. In our case, the proper diagnosis was made with the help of immunohistochemistry.

Normal bone marrow function over 6 years in a patient with dysplastic hematopoiesis and a complex karyotype.

Myelodysplasia associated with a complex karyotype is usually associated with advanced stage myelodysplastic syndrome (MDS) and an enhanced risk to develop secondary leukemia. We report on a 36-year-old female patient who was first presented in 1997 because of 'Pseudo Pelger-Huet' neutrophils. The remaining blood and differential counts were normal. Bone marrow examination revealed dysplasia in the erythroid and granulocytic series, no increase in blasts, and a karyotype with complex aberrations involving chromosomes 7, 13, 20 and 22. Almost all metaphases examined appeared to be affected. During the next few months, the patient was closely monitored and considered as candidate for bone marrow transplantation. However, blood counts remained stable without occurrence of significant cytopenias or an increase in blasts. Re-examinations of the bone marrow in 1998 and 1999 disclosed identical results compared to that obtained in 1997. After a total follow up of 6 years, the patient is still in good health with normal blood counts and persisting 'Pseudo Pelger-Huet' neutrophils. This exceptional case supports the notion that complex chromosomes are not invariably associated with rapid disease evolution in MDS.

Tuberculosis and Pelger-Huët anomaly. Case report.

We describe a patient with pulmonary tuberculosis and a rare disturbance of leukocyte segmentation, known as "Pelger-Huët anomaly", which can be observed in various diseases such as malignancies and/or infections. The importance of this association is equivocal: some authors have related to the association the particular severity of tuberculosis or the death they observed; in the case reported we noted no evidence of such a relation, notwithstanding the presence of the homozygous form of the Pelger-Huët anomaly. We suggest therefore that, when Pelger-Huët anomaly is found, an underlying disease should be searched for; the course of this illness, however, might not be affected.

Familial Pelger-Huet anomaly accompanied by tuberculosis and complicated by acute polyarthritis.

A patient with familial Pelger-Huet (PH) anomaly, which accompanied tuberculosis, and acute polyarthritis is described. Investigations surrounding this case suggests that the immunological abnormalities may be associated with the PH anomaly and the tuberculosis, and that the complications may be related to the development of the acute polyarthritis.

[The Pelger-Huët anomaly]. / Pozorování Pelger-Huëtovy anomálie.

The authors describe a case-history of Pelger-Huët anomaly in a 53-year-old patient with bronchogenic carcinoma. It was not possible to reveal whether an inborn or acquired anomaly was involved. Recent knowledge of this problem is discussed.

Pelger-Huët anomaly mimicking 'shift to the left'.

A case report is presented of an 83-year-old male patient with respiratory distress, body temperature of 38.5 degrees C, bilateral white infiltrates on chest X-ray and ECG showing acute myocardial infarction. Clinical evaluation led to the suspicion of severe infection accompanying lung congestion due to the infarction, mostly because his white blood cell differential count showed a persistent severe 'shift to the left'. Re-examination of his blood smear showed that the 'shift to the left' did not consist of band forms but of a 'Pelger-Huet' anomaly of the granulocytes. Recognition of this anomaly in the light of rapid clinical and radiological improvement precluded the administration of antibiotics for the diagnosis of severe infection with pulmonary involvement, which responded to diuretic therapy alone.

[Pelger-Huët anomaly and hereditary elliptocytosis in 2 siblings]. / Anomalía de Pelger-Huët y eliptocitosis hereditaria en 2 hermanos.

The Pelger-Huët anomaly (PHA) and the hereditary elliptocytosis (HE) are alterations affecting leukocytes and erythrocytes, respectively. Most of the affected individuals do not present clinic manifestations and are casually detected in the laboratory. The PHA and HE were described related to other hereditary and congenital conditions, but rarely have been found in the same individual. In this paper are reported discovery of the PHA and HE combined both in sister and brother, with global delay of development and peculiar physical characteristics. Blood smears of both showed an increase of bilobed neutrophils and elliptic erythrocytes. The family study showed two more members of the mother's branch affected with HE. The PHA could not be found in the parents, nor the other members of both branches. The early deaths or in uterus of three sibs of the propositus are appointed. The absence of the PHA in both parents of the affected individuals,--without discarding the illitimacy possibility--, can be explained by an incomplete genetic penetrance. The early or in uterus deaths of three sibs of the propositus seems possible that in some cases the combination of PHA and HE could be lethal. Possibly in Mexico this may be the first report of the presentation of the PHA and HE simultaneously in the same individual.

[Myelodysplastic syndrome in a patient with familial Pelger-Huet anomaly].

This paper reports on a patients with congenital Pelger-Huet anomaly who developed myelodysplastic syndrome (MDS). A 45-year-old female was referred for investigation of pancytopenia of 6 months' duration. Hereditary Pelger-Huet anomaly was diagnosed by family study 7 years prior to admission. On admission, Hb was 6.5 g/dl, Ht 19.9%, Platelets 1.8 x 10(4)/microliters, and WBC 1,200/microliters with 2% myelocytes, 9% metamyelocytes, 14% bands, 2% segmented neutrophils, 58% lymphocytes and 5% monocytes. Most of the granulocytes were Pelger-Huet type with strikingly clumped nuclear chromatin. Bone marrow aspirate demonstrated 3.6% blasts and dysplastic changes including megaloblastoid features in erythroid series and micro-megakaryocytes compatible with refractory anemia, a subtype of MDS. The association of hereditary Pelger-Huet anomaly and MDS is discussed.