Holoprosencephaly

A 26-year-old gravida 2, para 1 woman was referred to the Medical Genetics Clinic for consultation at 25 weeks of gestation for a questionable "double bubble" (gastric and duodenal distension proximal to a presumed atretic site) that was observed on ultrasound examination. A repeat ultrasound examination revealed a fetus growing appropriately for gestational age but with an echogenic bowel. The double bubble was not seen, but a fluid-filled structure was identified, probably representing a distended gallbladder. The family history revealed no birth defects or mental retardation. This woman's first child was alive with no abnormalities. The mother declined amniocentesis. Because of the echogenic fetal bowel, maternal blood was drawn to evaluate titers for toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex infection and to search for cystic fibrosis mutations. Because of partial French-Canadian ancestry, she was also tested for Tay-Sachs carrier status. Results of all those tests were normal or negative.

A 2750-g girl was born at 35 weeks' gestation by normal vaginal route. Apgar scores were 4 at 1 minute, 6 at 5 minutes (after intubation), and 8 at 10 minutes. Postaxial polydactyly of all 4 extremities was noted, and echocardiography for respiratory distress and hypotension revealed tetralogy of Fallot. At this point, it was thought that the child might have either Edwards syndrome or Patau syndrome. The cardiac malformation greatly compromised her condition, resulting in refractory hypotension and hypoxemia, and the family decided to withdraw ventilator support. A few hours after her death, the Genetics Laboratory reported preliminary fluorescent in situ hybridization findings consistent with trisomy 13 (Patau syndrome) (Figure, A: fluorescent in situ hybiridization image of a cell showing +13; the green signal is the 13 probe and the orange signal is the 21 probe). The final karyotype report confirmed the trisomy 13 (Figure, B). Review of a peripheral smear revealed 2 or more small threadlike projections from the nuclei in more than 80% of the neutrophils (Figure, C).

Trisomy 13 usually occurs by nondisjunction during gametogenesis. The prognosis is poor. Fetal death is frequent, and 90% of these babies that are born alive die within 1 year. Most have severe brain anomalies (especially holoprosencephaly). Heart defects, polydactyly and other limb anomalies, facial clefting, abdominal wall defects, and kidney malformations are also common. Any affected child may have some but not all of these problems. If the child survives the early weeks, growth is slow, and healing of wounds and recovery from illness are compromised. The few who live longer do not usually walk or speak meaningfully. Thus, they are significantly more severely handicapped than most children with Down syndrome.1

Huehns et al2 reported numerous pedunculated nuclear projections attached to the surface of nuclei in neutrophils of persons with trisomy 13. Electron microscopic examination revealed the presence of chromatin in these projections. Huehns et al2 concluded that this feature is specific to trisomy 13. Walzer et aP proposed that a finding of 2 or more projections in 15% of the leukocytes is highly suggestive of D^sub 1^ trisomy. In normal females, 2% to 10% of mature neutrophils exhibit a single drumstick (nuclear projection) (Figure, D), representing the inactivated X chromosome.

A pathologist's identification of structural anomalies of the neutrophils on a blood smear can provide rapid (less than 1 hour) support to the clinical suspicion of trisomy 13. This information may assist clinicians and families facing complex decisions about life support or transport after the delivery of an infant with multiple anomalies. Even in the most advanced centers, a fluorescent in-situ hybridization report usually requires 24 hours to obtain.

References

1. Baty BJ, Brent BL, Carey JC. Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet. 1994;49:175-188.

2. Huehns ER, Lutzner M, Hecht F. Nuclear abnormalities of the neutrophils in D^sub 1^ (13-15) trisomy syndrome. Lancet 1964;13:589-590.

3. Walzer S, Gerald PS, Breau G, O'Neill D, Diamond LK. Hematologic changes in the trisomy syndrome. Pediatrics. 1966;38:419-429.

Mohamed E. Salama, MD; Veena Shah, MD; Robert Roger Lebel, MD, FACMG; Daniel L. VanDyke, PhD, FACMG

Accepted for publication October 1, 2003.

From the Departments of Pathology and Medical Genetics, Henry Ford Hospital, Detroit, Mich.

Reprints: Mohamed E. Salama, MD, Department of Pathology K-6, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202 (e-mail: msalama1@hfhs.org).

Copyright College of American Pathologists Feb 2004
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