Article Text

Microdeletion 22q11.2: clinical data and deletion size
  1. W S KERSTJENS-FREDERIKSE
  1. Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands; and Hospital for Sick Children, University of Toronto Canada
  2. Biomedical Research Center, Osaka University Medical School, Japan
  3. Children’s Hospital of Philadelphia and University of Pennsylvania, USA
  4. Princess Margaret Hospital, University of Toronto, Canada
  5. Hospital for Sick Children, University of Toronto, Canada
    1. H KURAHASHI
    1. Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands; and Hospital for Sick Children, University of Toronto Canada
    2. Biomedical Research Center, Osaka University Medical School, Japan
    3. Children’s Hospital of Philadelphia and University of Pennsylvania, USA
    4. Princess Margaret Hospital, University of Toronto, Canada
    5. Hospital for Sick Children, University of Toronto, Canada
      1. D A DRISCOLL,
      2. M L BUDARF,
      3. B S EMANUEL
      1. Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands; and Hospital for Sick Children, University of Toronto Canada
      2. Biomedical Research Center, Osaka University Medical School, Japan
      3. Children’s Hospital of Philadelphia and University of Pennsylvania, USA
      4. Princess Margaret Hospital, University of Toronto, Canada
      5. Hospital for Sick Children, University of Toronto, Canada
        1. B BEATTY,
        2. T SCHEIDL
        1. Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands; and Hospital for Sick Children, University of Toronto Canada
        2. Biomedical Research Center, Osaka University Medical School, Japan
        3. Children’s Hospital of Philadelphia and University of Pennsylvania, USA
        4. Princess Margaret Hospital, University of Toronto, Canada
        5. Hospital for Sick Children, University of Toronto, Canada
          1. J SIEGEL-BARTELT,
          2. K HENDERSON,
          3. C CYTRYNBAUM,
          4. G NIE,
          5. I TESHIMA
          1. Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands; and Hospital for Sick Children, University of Toronto Canada
          2. Biomedical Research Center, Osaka University Medical School, Japan
          3. Children’s Hospital of Philadelphia and University of Pennsylvania, USA
          4. Princess Margaret Hospital, University of Toronto, Canada
          5. Hospital for Sick Children, University of Toronto, Canada

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            Editor—Ninety probands with microdeletion 22 were ascertained at The Hospital for Sick Children, Toronto, between 1 January 1994 and 1 June 1997. All patients had been karyotyped by G banding and were found to have a 46,XX or 46,XY karyotype except for one patient who had a de novo unbalanced translocation: 45,XY,der(6) t(6;22)(p25;q11.2)/45,XY,der(6)t(6;22)(p25;q11.2),+f. The fragment was very small and was not defined. All were shown by FISH analysis to be deleted for D22S75 using probe N25 (Oncor, Gaithersburg, MD). FISH analysis for D22S75 was also performed on 126 parents of 73 probands. The study was approved by the Research Ethics Board of the hospital and written informed consent was obtained.

            Clinical data were reviewed retrospectively in 90 cases. Forty five (50%) were female and 45 (50%) male. The median age at diagnosis was 5.5 years, with 23 cases (26%) under the age of 1 year. The height in relation to age was lower than average, with 69/85 cases (81%) being less than the 50th centile (no data in five cases). Head circumference was less than the 50th centile in 56/80 cases (70%) (no data in 12 cases). Data on palatal abnormalities/hypernasal speech were available in 72 cases with no data in 18 cases. Palatal abnormalities/hypernasal speech were found in 55/72 cases (76%): 28 patients had hypernasal speech without cleft, four a bifid uvula, 12 a submucous cleft, eight an overt cleft palate, and three a cleft lip and palate. Because nasal endoscopy to include or exclude a submucous cleft was not performed under the age of 6 years, data from those under 6 years of age and those 6 years and over were assessed separately. Palatal abnormalities/hypernasal speech were found in 21/33 (64%) of those under 6 years of age and in 34/39 (87%) of those 6 years of age or above. Of the 18/90 cases (20%) for which no data were available, the chart did not contain a statement that the palate was normal. Of these, 17 were from the younger and one was from the older age group. A heart defect was found in 60 patients (67%). A renal ultrasound was performed in 33 cases, which showed abnormalities in eight (24%).

            Development was scored as abnormal if motor milestones were more than six months delayed, or special education was needed, or psychiatric disease was diagnosed. Cases without follow up beyond the age of 1 year were scored as “no data”. Because mild mental impairment may not be evident in infancy and in very early childhood, patients were separated into two groups to evaluate development: those under 3 years of age (n=34) and those 3 years of age or over (n=56). In the group under 3 years of age, insufficient data were available in 23 cases, eight cases showed developmental concerns, and two had age appropriate development. In the 56 cases 3 years of age or over, 48 were abnormal and eight were normal.

            Table 1 summarises the less common clinical findings in this study; some may be coincidental. However, all of these findings have been reported in association with the deletion in other studies.1-4

            Table 1

            Uncommon clinical features in study patients

            FISH analysis was performed on metaphases from cultured lymphocytes according to standard protocols5 on 76/90 (84%) of the probands. Cosmid probes pH11 (D22S36), H2 (HCF2), cHKAD26,6 and LN80 (D22S801) within 22q11.2 and a control probe pH17 (D22S39) within 22q13 were used. Order of the loci from centromere to telomere are as follows: D22S36, D22S75, HCF2 and cHKAD26, D22S801//D22S39. D22S36 is considered to lie 450-650 kb distal to D22S427,7 whereas HCF2 and cHKAD26 (relative position to each other not unequivocally known) are close to D22S311.8-10 A minimum of 10 metaphases were analysed after selection for a positive signal at the control locus. Mosaicism was not ruled out. Three types of deletions were found. A large deletion that included D22S36, D22S75, HCF2, cHKAD26, but not D22S801 was found in 64/76 probands (84%). A proximal deletion that included D22S36 and D22S75 but not HCF2, cHKAD26, and D22S801 was found in 11/76 probands (14%). In one patient, this proximal deletion was secondary to an unbalanced reciprocal translocation. An intermediate deletion that included D22S75, HCF2, and cHKAD26 but not D22S36 and D22S801 was found in one case. The large and proximal deletions are consistent with the 3 Mb and 1.5 Mb deletions reported.10 11

            Seven of the deletions were found to be familial, five maternal and two paternal. Sib occurrence was found in four families. The large common deletion was found in 6/7 familial cases and included a family with a 9 year old boy with normal development whose father with the deletion was a secondary school teacher. The father has a repaired cleft palate and mild facial features as his only clinical manifestations. Clinical data of the 12 cases with deletions involving fewer of the tested loci are summarised in table 2. The case with the intermediate deletion (case 12 in table 2) presented at the age of 20 years with hypocalcaemia, owing to partial hypoparathyroidism. Hypothyroidism requiring medication had been previously detected. He had been born at 33 weeks gestation and had required repair of bilateral inguinal hernias during infancy. A vesicoureteral reflux was diagnosed. His school performance was not as good as his unaffected sister’s, but he completed high school and was working in a warehouse. He had a slightly long face with narrow palpebral fissures. His speech was hypernasal and he had a submucous cleft. With respect to the phenotypes of all the probands in this study, no correlation was found with deletion size, as in other studies.9 11

            Table 2

            Clinical data of patients with atypical deletions

            Deletions in microdeletion 22 are reported to be 2-3 Mb in size with several genes reported for the commonly deleted region. The shortest region of overlap of approximately 300 kb has been defined.12 13 A high level of interchromosomal rearrangements has been reported for the origin of deletion 22q11.214 and the presence of different deletions found in our study suggests that different repeat sequences may be used for unequal crossing over during meiosis. The range of clinical features seen in this study is consistent with that reported in large studies.1 How haploinsufficiency of a 2-3 Mb region can lead to such a wide range of clinical phenotypes in microdeletion 22 is unclear.

            Acknowledgments

            W S Kerstjens-Frederikse was supported by a grant from the Ter Meulen Fonds (The Netherlands). The study was supported in part by the following grants: SEED grant 97-012 from The Hospital for Sick Children, Canada, and grants DC02027 and HL51533 from the National Institutes of Health, USA.

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