Judy C. Hawkins

Position Effects Due to Chromosome Breakpoints that Map ∼900 Kb Upstream and ∼1.3 Mb Downstream of SOX9 in Two Patients with Campomelic Dysplasia

Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y–related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25.1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1::7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.

A Rapid and Noninvasive Method for Detecting Tissue-Limited Mosaicism: Detection of i(12)(p10) in Buccal Smear from a Child with Pallister-Killian Syndrome

Pallister-Killian syndrome (PKS), a rare disorder, is characterized by tissue-limited or tissue-specific mosaicism. The characteristic chromosome abnormality associated with PKS is i(12p), which is seen predominantly in skin fibroblast cultures. Diagnosis of i(12p) has been carried out on buccal smears before and was shown to be an easy and feasible method. All previously published studies used alpha-satellite probes for the diagnosis and as such have several pitfalls. Our approach, using dual-color, locus-specific probes, has high specificity and sensitivity for the diagnosis of i(12p). Using statistical analysis, we have also confirmed that the signal pattern in interphase nuclei is consistent with isochromosome 12p.

Prenatal Diagnosis of a Fetus with Unbalanced Translocation (4;13)(p16;q32) with Overlapping Features of Patau and Wolf-Hirschhorn Syndromes

Wolf-Hirschhorn syndrome (WHS) and Patau syndrome are two of the most severe conditions resulting from chromosome abnormalities. WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13. Though the etiologies of these syndromes differ, they share several features including pre- and postnatal growth retardation, microcephaly, cleft lip and palate, and cardiac anomalies. We present here a female fetus with deletion of 4p16 → pter and duplication of 13q32 → qter due to unbalanced segregation of t(4;13)(p16;q32) in the father. She displayed overlapping features of both of these syndromes on ultrasound. To the best of our knowledge, this is the first report of a fetus with both partial trisomy 13 and deletion of 4p16, the critical region for WHS.

Pericentric inversion, inv(14)(p11.2q22.3), in a 9-month old with features of Goldenhar syndrome.

Goldenhar syndrome, also called hemifacial microsomia or oculo-auriculo-verterbal dysplasia (OAVS) (MIM 164210), is a birth defect involving the first and second branchial arch derivatives with an incidence of 1/5000. The variable phenotype includes mostly unilateral deformity of the external ear and small ipsilateral half of the face with epibulbar dermoid and vertebral anomalies. A genome-wide search in one family suggested linkage to a region of 10.7 cM on chromosome 14q32; however, no candidate genes have been identified. We report on a 9-month old with OAVS and a pericentric inversion of chromosome 14 which he inherited from his phenotypically normal mother. Fluorescence in-situ hybridization analysis with bacterial artificial chromosome clones from chromosome 14 showed the breakpoint on 14q maps distal to 14q21.2, thus confirming the cytogenetic breakpoints. In light of previous linkage studies mapping OAVS to 14q, we propose that the long arm breakpoint in our proband disrupted a potential candidate gene for OAVS resulting in his clinical phenotype.

Partial trisomy and partial monosomy resulting from a reciprocal segregating in a large family

Partial trisomy 7p with partial monosomy 9p is a rare disorder with only 3 cases reported. Both these abnormalities i.e., partial trisomy 7p and partial monosomy 9p result in distinct clinical phenotypes. However, patients with combined 7p trisomy/9p monosomy present with a phenotype consistent with trisomy 7p. We present a fourth case of trisomy 7p/monosomy 9p with long term follow-up and document the medical complications associated with this disorder. Long term follow-up of patients with chromosome abnormalities provides a unique opportunity to document the medical history and complications associated with such abnormalities.

Founder Mutation R245H of Sanfilippo Syndrome Type A in the Cayman Islands

Sanfilippo A syndrome is an autosomal recessive lysosomal storage disease. This disease was reported in the Cayman Islands population with carrier frequency of 1/7 to 1/10 in the West Bay district of Grand Cayman. The carrier testing of Sanfilippo A disease for families at risk was carried out using the thermal characteristics of sulfamidase activity. In the present study, a search for mutations in the sulfamidase gene in an index family was performed. In addition, 77 individuals, relatives of children with Sanfilippo A syndrome, were also studied by single-strand conformation polymorphism (SSCP), restriction fragment-length polymorphism (RFLP) analyses, and sequencing. A single mutation, G746A (R245H), was found in the family, with the patient being homozygous and both parents and 1 of the 3 siblings being carriers. Among the 77 family members of the patient with Sanfilippo syndrome, the same mutation was found among carriers of the disease. The finding of a single mutation supports the idea of a founder effect, which facilitates accurate carrier identification of Sanfilippo A syndrome in the population of Cayman Islands.

First report of an interstitial deletion, del(5)(q33.1q35.1) in a girl with primary amenorrhea, seizures, and severe behavioral and developmental deficiencies†

Constitutional interstitial deletions of the long arm of chromosome 5 are extremely rare with only 36 cases reported [Courtens et al., 1998]. Deletions distal to 5q33 have been reported only in 10 patients [Joseph et al., 1990; Kleczkowska et al., 1993; Stratton et al., 1994; Giltay et al., 1997; Gibbons et al., 1999; Krammer et al., 1999; Pauli et al., 1999; Spranger et al., 2000; Schafer et al., 2001; Schiffer et al., 2003]. To our knowledge, there are no reports of constitutional interstitial deletion, del(5)(q33q35) in adolescents. Here, we report on a 17-year-old Caucasian female with del(5)(q33.1q35.1) presenting with primary amenorrhea, seizures, and severe behavioral and mental deficiencies. A 17-year-old, Caucasian girl was referred to genetics clinic because of failure to thrive and primary amenorrhea. She had a history of mental retardation, cerebral palsy and seizures. On physical examination, her weight was 34.7 kg (<5th centile), height was 150 cm (<5th centile), and head circumference was 52 cm (<5th centile). She had minor dysmorphic features including narrow face, deepset eyes, low-set ears, deviated nasal bridge, higharched palate, triangular face, and poor dentition. She also had clinodactyly of the 5th digit and flexion contractures of digits on the hands. She had Tanner III stage breast development. There were no other major organ malformations. However, she displayed very unusual behaviors, such as aggressive sexual behavior towards males and acting like a dog or cat by barking at people and licking her hands repeatedly. She could walk, but was very wobbly, and was not able to talk, write, or distinguish colors. She had a history of chronic diarrhea and constipation. Despite an enormous appetite, she had lost 9.1 kg within a span of 3 months secondary to diarrhea. Laboratory investigations included chromosome analysis, FISHstudies, serumaminoacidsandhormone levels. Serum amino acid screen showed high serum levels of threonine (24.8; normal 9.0–18.8 mmol/dl), glutamine (104.4; normal 21.5–82.5 mmol/dl), glycine (85.1; normal 17.2–41.0 mmol/dl), alanine (84.0; normal 22.7–53.7 mmol/dl), citrulline (4.5; normal 1.9–4.3 mmol/dl), alpha-amino-N-butyric acid (2.3; normal 1.0–2.2 mmol/dl); cystine (14.8; normal 3.4– 12.0mmol/dl), cystathionine (0.2mmol/dl), lysine (22.5; normal9.7–18.7mmol/dl), 1-CH3-histidine (2.2;normal 0–0.9 mmol/dl) and low serum levels of aspartic acid (1.2; normal 1.4–7.2 mmol/dl), and tyrosine (4.3; normal 4.4–10.6 mmol/dl). These results are suggestive of hepatic dysfunction although liver function tests were normal. Serum FSH and LH levels were normal while the estradiol was very low (8 pg/ml). Chromosome analysis from cultured peripheral blood lymphocytes showed an unbalanced structural rearrangement in all 20 cells analyzed. Based on

Book Review: When Your Child Has a Disability: The Complete Sourcebook of Daily and Medical Care (2nd Revised Edition). Edited by Mark L. Batshaw. Paul H. Brookes Publishing Company, Baltimore, Maryland 21285, 2001, 467 pp.,

Would not it be wonderful if there were a single book to recommend to any parent of a child with special needs? This title, When Your Child Has a Disability: The Complete Sourcebook of Daily and Medical Care , is certainly named to fit the bill. I expected that this volume would contain basic advice for parents regarding caring for a child with disabilities. In this volume I expected an explanation of the roles of different members of the health care team; simple information regarding insurance, advocacy, school and legal services; a parent-oriented reference regarding the use of medical appliances and their care; and possibly even a list of support organizations to contact for further information. This book does cover quite a few of these issues while additionally taking on the task of including information about many of the specific causes of childhood disability. This volume did, however, somewhat disappoint as it presents certain information in a confusing manner. The Editor, Dr. Mark Batshaw, a developmental pediatrician affiliated with Children’s National Medical Center, George Washington University, and Children’s Research Institute, heads an impressively well-rounded writing team drawing from specialized fields including developmental pediatrics; genetics; neurology; psychology; psychiatry; endocrinology; ophthalmology; dentistry; and physical, occupational, and speech therapy. Distinguished authors have contributed chapters covering areas of their expertise. This organization does introduce some discontinuity; however, as each family’s situation is unique, the book is designed as a reference and not so much a “cover to cover read.” The book is divided into four sections: “Getting the Diagnosis”; “Growing Up with a Disability”; “Developmental Disabilities”; and “What the Future Holds.” Each section presents facets of treatment through chapters devoted to more specific issues. For example, the section “Growing Up with a Disability” includes chapters on early intervention, nutrition and feeding, dental care, rehabilitation therapies, medications, behavior, and educational and legal rights. Chapters begin with an introductory summary and finish with a list of commonly asked questions with practical and insightful answers. Woven throughout the sections are vignettes depicting family situations appropriate to the text.

22.95 (paperback)

1 A.W. Liley Medal 2001 Awarded to Prof. Wolfgang Holzgreve Chervenak, F.A. (New York, N.Y.) 3 Prenatal and Perinatal Aspects of a Giant Fetal Cervicothoracal Lymphangioma Axt-Fliedner, R.; Hendrik, H.J.; Schwaiger, C.; Ertan, A.K.; Friedrich, M.; Schmidt, W. (Homburg/Saar) 8 Gelatin Sponge Embolization. A Method for the Management of Iatrogenic Preterm Premature Rupture of the Membranes O’Brien, J.M.; Milligan, D.A.; Barton, J.R. (Lexington, Ky.) 11 Diagnostic and Therapeutic Dilemma with Large Prenatally Detected Cystic Adrenal Masses de Luca, J.L.; Rousseau, T.; Durand, C.; Sagot, P.; Sapin, E. (Dijon) 17 The Influence of Smoking and Parity on Serum Markers for Down’s Syndrome Screening Tišlarić, D. (Zagreb); Brajenović-Milić, B.; Ristić, S. (Rijeka); Latin, V. (Zagreb); ZZ uvić-Butorac, M.; BacZ ić, J. (Rijeka); Petek, M. (Zagreb); Kapović, M. (Rijeka) 22 Erythropoietin as Treatment for Late Hyporegenerative Anemia in Neonates with Rh Hemolytic Disease after in utero Exchange Transfusion Nicaise, C.; Gire, C.; Casha, P.; d’Ercole, C.; Chau, C.; Palix, C. (Marseille) 25 Alpha-Fetoprotein Values in Amniotic Fluid Obtained during Early Amniocentesis (11–13 Weeks) Nwebube, N.I.; Lockitch, G.; Halstead, C. (Vancouver); Johnson, J. (Toronto); Wilson, R.D. (Vancouver) 29 Prenatal Diagnosis of Arthrogryposis multiplex congenita with Increased Nuchal Translucency but without Any Underlying Fetal Neurogenic or Myogenic Pathology Madazl}, R.; Tüysüz, B.; Aksoy, F.; Barbaros, M.; UludagE , S.; Ocak, V. (Istanbul) 34 Prenatal Diagnosis of Lissencephaly (Type II) by Ultrasound and Fast Magnetic Resonance Imaging Kojima, K.; Suzuki, Y.; Seki, K.; Yamamoto, T.; Sato, T.; Tanaka, T.; Suzumori, K. (Nagoya) 37 Expression of C-Type Natriuretic Peptide in Human Placenta and Myometrium in Normal Pregnancies and Pregnancies Complicated by Intrauterine Growth Retardation. Preliminary Results Stepan, H.; Faber, R.; Stegemann, S. (Leipzig); Schultheiss, H.-P.; Walther, T. (Berlin) 42 Early Transvaginal Biometry of Fetal Orbits: A Cross-Sectional Study Guariglia, L.; Rosati, P. (Rome) 48 Uterine Artery Doppler Velocimetry in Patients with Idiopathic Hydramnios Hershkovitz, R.; Sheiner, E.; Furman, B.; Smolin, A.; Hallak, M.; Mazor, M. (Beer-Sheva) 52 First-Trimester Ductus venosus Velocimetry in Relation to Nuchal Translucency Thickness and Fetal Karyotype Zoppi, M.A.; Putzolu, M.; Ibba, R.M.; Floris, M.; Monni, G. (Cagliari) 58 MR Autopsy in Fetuses Huisman, T.A.G.M.; Wisser, J.; Stallmach, T.; Krestin, G.P.; Huch, R.; Kubik-Huch, R.A. (Zürich) No. 2