Journal of Perinatology (2012) 32, 238–240 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION A neonate with the Pelger–Hue¨t anomaly, cleft lip and palate, and agenesis of the corpus callosum, with a chromosomal microdeletion involving 1q41 to 1q42.12 RD Christensen1 and HM Yaish2 1Department of Women and Newborns, Intermountain Healthcare, Salt Lake City, UT, USA and 2Primary Children’s Medical Center and the Department of Pediatrics, Division of Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, UT, USA cyanotic and hypotonic with Apgar scores of 1, 5, 6 and 7 (at 1, 5, We observed a neonate with cleft lip and palate, 13 sets of ribs, agenesis of 10 and 15 min). Birth weight was 3177 g (38th percentile), length the corpus callosum, slightly small penis, hypoglycemia, and what initially 48 cm (37th percentile) and occipitofrontal circumference 35 cm appeared to be a marked leukocyte ‘left shift’ on complete blood count, but (67th percentile). The umbilical cord arterial blood had a pH 6.99 which was actually a Pelger–Hue¨t anomaly. A chromosomal microdeletion with a base deficit of À14.4 mmol lÀ1. When the respiratory was identified at1q41-42.12. distress and cyanosis continued despite mask continuous positive Journal of Perinatology (2012) 32, 238–240; doi:10.1038/jp.2011.119 airway pressure application, endotracheal intubation and Keywords: cleft lip and palate; Pelger-Hue¨t; microdeletion mechanical ventilation were provided and umbilical catheters were placed. The CBC showed a neutrophil concentration of 13.2 Â 103 per Introduction ml with 12% segmented neutrophils, 45% band neutrophils, À1 When newborn infants are evaluated for sepsis they generally have hemoglobin 12.6 g dl , hematocrit 40.5%, mean corpuscular volume 95.1 fl, mean corpuscular hemoglobin 29.9 pg, mean a complete blood count (CBC) performed looking for, among À1 1 corpuscular hemoglobin concentration 31.1 g dl , platelets other elements, a leukocyte ‘left shift’. Indeed, the diagnosis of 3 neonatal infection is supported by the finding that the circulating 181 Â 10 per ml and 113 nucleated red blood cells (NRBC)/100 white blood cells. The presentation with flaccidity, acidosis, neutrophils are predominantly band forms and metamyelocytes, 4 with fewer segmented neutrophils.2,3 respiratory failure and elevated NRBC were interpreted as We cared for a term neonate admitted to the NICU because consistent with umbilical cord compression in utero. Intravenous of respiratory distress. A severe cleft lip and palate and a variety antibiotics were administered, with the suspicion of bacterial of minor dysmorphic features were recognized. The initial CBC sepsis and pneumonia. showed a ‘left shift’ as did all subsequent CBCs but evaluation The initial blood glucose concentration measured 120 min following delivery, with no intravenous fluids yet running, was revealed no evidence of infection. Cytogenetic studies showed a 1q4 À1 À1 microdeletion including the genes we propose are responsible for 1mgdl . Dextrose-containing fluids were bolused (2 ml kg the features of this syndrome. intravenous) and the intravenous dextrose infusion rate was increased to 8 and then to 13 mg kgÀ1 per min with an increase in blood glucose to 200 mg dlÀ1. Serum electrolytes were normal and remained so during the hospitalization. Case Over the first 3 days, all cultures of blood, tracheal aspirate The patient was delivered by repeat cesarean section without labor and urine, were sterile. Cultures for cytomegalovirus, herpes, at 39.0 weeks gestation to a married 35 year old G4 P3003 healthy mycoplasma and ureaplasma were also negative. The CBC Caucasian. A cleft lip and palate had been detected by ultrasound continued to have a leukocyte ‘left shift’ despite clinical at 20 weeks gestation. The patient’s mother’s brother was born with improvement, including extubation to room air, weaning and a cleft lip and palate 24 years earlier. At delivery the baby was discontinuation of the intravenous solution and feedings of expressed mother’s milk using a Haberman feeder. Correspondence: Dr RD Christensen, Department of Women and Newborns, Intermountain Cranial ultrasound examination on day of life 2 suggested Healthcare, 4401 Harrison Boulevard, Salt Lake City, UT 84403, USA. E-mail: [email protected] agenesis of the corpus callosum. The initial cardiac echo showed Received 15 July 2011; accepted 25 July 2011 a patent ductus arteriosis and an atrial septal defect. A repeat echo Pelger–Hue¨t anomaly and 1q4 deletion RD Christensen and HM Yaish 239 film, where characteristic findings are observed in neutrophils; unilobed or bilobed (Pince–Nez) nuclei with clumped nuclear chromatin. Similar nuclear changes are sometimes seen in neutrophils of individuals with leukemia, lymphoma, malaria, metastatic disease or Sjogren’s syndrome, and can be induced by drugs such as colchicine.8,9 Disruption of genes near the lamin B receptor gene, at 1q41-44, has been associated with midline craniofacial abnormalities.10 Kalfa et al. recently reported a 10-month old with a constellation of findings and a microdeletion very similar to our case, but the two cases are discordant in some features including 13 sets of ribs in ours and hypoplastic nails and clinodactyly in theirs.11 Figure 1 Photomicrograph of a blood film demonstrating hypolobulation of Mazzeu et al.12 reported two children with deletions encompassing neutrophils with coarse nuclear chromatin and a ‘Pince–Nez’ nucleus 1q41q42.1 with features of Robinow syndrome but with no mention (resembling spectacles). of the Pelger–Hue¨t anomaly or midline craniofacial clefting. We speculate that other children with cleft lip and palate might 2 weeks later showed the ductus arteriosis had closed. have an unrecognized microdeletion involving the 1q4 region. Chest X-rays revealed 13 sets of ribs. Penile length was 2.5 cm Certainly if a child with cleft lip and palate were to have the (2 s.d. below mean5). Pelger–Hue¨t anomaly, a 1q4 deletion would be likely, because of Blood films were consistent with the Pelger–Hue¨t anomaly the proximity of relevant genes. Identifying individuals with cleft (Figure 1) with no nuclear lobulation beyond the bilobed stage, lip and palate who have an associated 1q4 microdeletion could be and with typical Pince–Nez nuclei with highly clumped of value, because the condition would likely be heritable from the chromatin.6 proband in an autosomal dominant fashion. We also speculate that Serum cortisol on day of life 1 was 10.1 mgdlÀ1 (normal) and recognizing the Pelger–Hue¨t anomaly in a neonate can be useful on day 7 was 16.2 mgdlÀ1 (normal). Growth hormone on day of whether or not it is part of the 1q4 syndrome. Recognizing life 8 was 13.2 ng mlÀ1 (normal). Magnetic resonance imaging this anomaly can avoid confusion with a leukocyte ‘left shift’, of the head on day of life 13 showed absence of the middle and supporting the dictum to ‘treat the patientynot the posterior portions of the corpus callosum and a somewhat small laboratory test’. cerebellar vermis. On day of life 4, ARUP Laboratories (Salt Lake City, UT, USA) perfomed whole genome chromosomal microarray analysis using Conflict of interest Affymetrix methodology and software (genotyping Console and The authors declare no conflict of interest. Chromosome Analysis Suite, Affymetrix, Santa Clara, CA, USA). The array includes over 2.1 Â 106 markers across the entire genome. A microdeletion was identified on chromosome 1, involving a References 3.0-Mb segment from 1q41 to 1q42.12, indicating partial monosomy for this region. The deleted region includes the lamin 1 CDC. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR. Centers for Disease Control and Prevention, Atlanta, GA, B receptor gene (causing the Pelger–Hue¨t anomaly). Other deleted 19 November 2010; 59. CDC, 10. genes include LOC440926, FBX028, Clorf65, SUSD4, ENAH, 2 Manroe BL, Rosenfeld CR, Weinberg AG, Browne R. The differential leukocyte count DNAH14, CAPN2, Clorf55, EPHX1, DEGS1, ENAH, CNIH3, in the assessment and outcome of early-onset neonatal group B streptococcal disease. PYCR2, TMEM63A, TLR5, and ACSD3. J Pediatr 1977; 91: 632–637. 3 Christensen RD, Bradley PP, Rothstein G. The leukocyte left shift in clinical and experimental neonatal sepsis. J Pediatr 1981; 98: 101–105. Discussion 4 Christensen RD, Henry E, Andres RL, Bennett ST. Reference ranges for blood concentrations of nucleated red blood cells in neonates. Neonatology 2010; 99: The Pelger–Hue¨t anomaly results from mutations in the lamin B 289–294. receptor gene.6 Most often, the genetic basis for this anomaly is a 5 Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn missence mutation, resulting in a heterozygous condition heritable male infants. J Pediatr 1975; 86: 395–398. in autosomal dominant fashion. The Pelger–Hue¨t anomaly is a 6 Speeckaert MM, Verhelst C, Koch A, Speeckaert R, Lacquet F. Pelger-Huet anomaly: a critical review of the literature. Acta Haematol 2009; 121: 202–206. benign finding but can be confused with a leukocyte ‘left shift’, 7 Mohamed IS, Wynn RJ, Cominsky K, Reynolds AM, Ryan RM, Kumar VH et al. 1–3,7 which in a neonate suggests the presence of bacterial sepsis. White blood cell left shift in a neonate: a case of mistaken identity. J Perinatol 2006; The anomaly is generally recognized upon examining a blood 26: 378–380. Journal of Perinatology Pelger–Hue¨t anomaly and 1q4 deletion RD Christensen and HM Yaish 240 8 Skubitz KM. Qualitative disorders of leukocytes In: Greer JP, Forester J, Rodgers GM, comparison to the 1q41q42 microdeletion suggests a contiguous 1q4 syndrome. Paraskevas F, Glader B, Arber DA, Means, RT Jr., (eds). Wintrobe’s Clinical Am J Med Genet A 2010; 152: 987–993.