1. Review of the literature revealed a very similar case described by Le and Kutteh in 1996 4. They described a Hispanic male premature newborn with ambiguous genitalia, adrenal hypoplasia, anemia, thrombocytopenia, dysmorphic features and monosomy 7 in the bone marrow. Olshanskaya et al 5 described an 11-year old girl with XY gonadal dysgenesis and MDS with monosomy 7 in the bone marrow. Literature Review: Mosaic monosomy 7 in a male infant with ambiguous genitalia and multiple congenital anomalies DM LaGrave 1, CW Booth 2, DA Rita 2, ME Aston 1, KB Geiersbach 1,4, S. Shetty 1,4, LR Rowe 5, ST South 1,3,4 1 Cytogenetics and Molecular Cytogenetics, ARUP Laboratories, Salt Lake City, UT; 2 Lutheran General Hospital, Park Ridge, Ill, 3 Department of Pediatrics, University of Utah, Salt Lake City, UT, 4 Dept of Pathology, University of Utah, Salt Lake City, UT, 5 ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT Male Hispanic infant delivered at 27w4d by emergency c-section due to IUGR, decreased fetal movement and bradycardia. Clinical findings:  Ambiguous genitalia Perineoscrotal hypospadias with bifid scrotum  Bilateral clubfoot  Hyperpigmentation  Small, echogenic kidneys with pyelectasis  PDA  Brain MRI: Normal for age  Small thymus  Slow growth  Repeated episodes of sepsis, apnea and bradycardia  Low cortisol  Persistent absolute lymphopenia and thrombocytopenia  Chronic anemia of unknown etiology At 5 months of age (2 months - corrected age) he developed hypernatremia and became unresponsive. The parents elected to discontinue extraordinary measures, and the infant died. Postmortem examination was declined. Case Report: 1.Constitutional mosaic monosomy 7  Congenital anomalies suggest a constitutional anomaly  Deletion of the long arm of ch7 is associated with hypospadias, microphallus, and small scrotum  Explains all clinical findings 2.Pre-neoplastic change restricted to the bone marrow  Chronic, unexplained anemia, lymphopenia and thrombocytopenia  Monosomy 7 is the most common finding childhood MPS/MDS  Monosomy 7 syndrome?  Requires separate explanation for congenital anomalies  Normal male karyotype (performed prenatally on amniotic fluid and postnatally on peripheral blood)  DEB-induced breakage studies were normal  Array CGH Cyto6000 array platform (hg 18) 44k oligo array Performed on uncultured blood  RESULTS: Mosaic loss of one chromosome 7 (Fig 1)  Findings were confirmed using the CEP7 (centromere) FISH probe (Abbott Molecular) Direct, unstimulated bloodsmear: 1 signal in 84% of cells Cultured interterphase cells (Fig 2) oOne CEP7 signal in 80% of cells oTwo CEP7 signals in metaphase cells otwo normal-appearing chromosome sevens by karyotype analysis (Fig 3)  FISH on buccal cells CEP7 and D7S486 (7q31) 200/200 cells demonstrated 2 signals for each probe  STR analysis of sample demonstrated the presence of two different chromosome sevens in the disomic cells (Fig 4) Laboratory Testing and Results: Do the findings in this child represent a constitutional mosaic monosomy 7 or a pre-neoplastic change in the bone marrow only with concurrent, unrelated congenital anomalies? If the mosaicism is constitutional, then there are two possible etiologies: 1) monosomy rescue and 2) post-zygotic loss. Monosomy rescue was ruled out by STR analysis (Fig 4), leaving the possibility that a constitutional monosomic cell line began at some point during embryogenesis. If the monosomic cell line is restricted to the bone marrow, that would indicate that the congenital anomalies seen in the infant were coincidental and unrelated to the aCGH findings. Is this a possible new syndrome? We propose that the constellation of findings in this child represent a new genetic syndrome of development requiring a cell-line during embryogenesis that becomes monosomic for chromosome 7. The monosomic cell line could theoretically be due to monosomy rescue or post-zygotic loss, and its presence would be predicted to cause congenital anomalies of varying severity depending on the timing of rescue/loss and the level of mosaicism in different tissues at critical points in development. As the bone marrow is one tissue that can support a monosomy 7 cell line with little effect on fetal development, hyperplasia of the bone marrow leading to thrombocytopenia, anemia and/or lymphopenia would be expected to be a key finding in this syndrome. Genetic males with this syndrome would be expected to have some level of feminization of their external genitalia - possibly secondary to adrenal insufficiency. But the degree of feminization, if present, would depend on the variations in timing and tissues affected by the chromosome loss. Genetic females would be predicted to have normal genitalia but might demonstrate decreased cortisol levels in infancy. Discussion: Conclusions:  Male, Hispanic infant with mosaic monosomy 7, possibly limited to the bone marrow, and ambiguous genitalia  One other case, with very similar findings, described in the literature  A second case in the literature describing a girl with gonadal dysgenesis and monosomy 7 (45,XY,-7 in bone marrow analysis only) possibly representing a milder form of this proposed syndrome?  We propose that the rare association of ambiguous genitalia with monosomy 7 syndrome may be due to the prenatal loss of one chromosome 7 in affected children and would therefore represent a new genetic syndrome of development  Key features of the syndrome would be 1) monosomy 7 syndrome with hyperplasia of the bone marrow 2) genetic males with some degree of feminization of the external genitalia 3) +/- dysmorphic features 4) +/- adrenal hypoplasia  The key finding of ambiguous genitalia in males with mosaic monosomy 7 is similar to males with partial deletions of 7q suggesting that the mosaic monosomy 7 seen in the bone marrow was originally due to loss of chromosome 7 in an embryonic cell line Differential Diagnosis:. Fig 4 STR plots from 2 of 10 loci tested on chromosome 7. Plots demonstrate the presence of a two, unique chromosome sevens Monosomy 7 Syndrome 1, 2, 3  Monosomy 7 syndrome (Mo7s) has been described as a well-defined myeloproliferative disorder with prominent bone marrow dysplasia and hepatosplenomeagly existing primarily in young children  There is a significant disparity in the male to female ratio, with 70% of affected children being male  There are many clinical and epidemiologic similarities between Mo7s and juvenile chronic myelogenous leukemia. Monosomy7 is associated with genetic disorders of myelopoiesis that carry a high risk of myeloid leukemia (Fanconi anemia, severe congenital neutropenia, Shwachman-Diamond syndrome) as well as with constitutional conditions (neurofibromatosis, type 1; Down syndrome - possibly)  Familial bone marrow monosomy 7 has been observed in some families as a unique finding as well as being associated with cerebellar ataxia in others  Loss of chromosome 7, alone, is not sufficient for transformation to full leukemia a. aCGH: Chromosome 7b. Close-up view of Chromosome 7 by aCGH indicating mosaicism for monosomy 7 Fig 1 Fig 3 Banded chromosomes demonstrating 2 copies of chromosome 7 Fig 2 FISH (CEP7) demonstrating a single signal for chromosome 7 in one interphase cell and 2 signals in both an interphase cell and a metaphase cell 1.Daghistani D, Toledano SR, Curless R. Monosomy 7 syndrome. Clinical heterogeneity in children and adolescents Cancer Genet Cytogenet (1990) 44:263-9 2.Luna-Fineman S, Shannon KM, Lange BJ. Childhood Monosomy 7: Epidemiology, Biology, and Mechanistic Implications Blood, (1995) 85:1985-1999 3.Groupe Français de Cytogénétique Hématologique. Forty-four cases of childhood myelodysplasia with cytogenetics, documented by the Groupe Français de Cytogénétique Hématologique Leukemia (1997) 11:1478-1485 4.Le SQ & Kutteh WH. Monosomy 7 syndrome associated with congenital adrenal hypoplasia and male pseudohermaphroditism Obstet Gynecol (1996) 87:854-856 5.Olshanskaya YV, Udovichenko AI, Kolosova AV. Myelodysplastic syndrome with monosomy 7 in a patient with XY gonadal dysgenesis (incomplete testicular feminization) Cancer Genetics and Cytogenetics (2009) 191:113-114 References: