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Monosomy and trisomy 1q44-qter in two sisters originating from a half cryptic 1q;15p translocation
  1. * Cytogenetic Laboratory, S Gerardo Hospital, Via Solferino 16, 20052 Monza, Italy
  2. Paediatric Clinic, S Gerardo Hospital, Monza, Italy
  3. Neuropsychiatric Clinic, SGerardo Hospital, Monza, Italy
  4. § Department of Biology and Genetics for Medical Sciences, University of Milan, Via Viotti 3/5, 20133 Milan, Italy
  1. Dr Dalprà, leda.dalpra{at}

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Editor—Cryptic translocations usually involve the telomeric regions of chromosomes and are not easy to detect by means of conventional cytogenetics.1 2 The published cryptic translocations have been identified through a phenotype corresponding to a chromosome deletion syndrome or as a result of the observation of an anomalous chromosome, in which case they are known as half cryptic translocations because only one of the chromosomes involved can be seen cytogenetically. The presence of satellites at the p or q end of non-acrocentric chromosomes seems to be quite a common phenomenon3 4 and represents a type of half cryptic translocation that signals a rearrangement between the satellited chromosome and one of the acrocentrics.

We describe here a family with a half cryptic translocation detected through a dysmorphic child. The reproductive history of the couple and their family was unremarkable.

The proband was the second child of the couple (daughter 1); the first was a phenotypically normal male and the third was a female with a mildly abnormal phenotype (daughter 2). The third month of gestation was characterised by a threatened miscarriage and the seventh by threatened premature labour. Spontaneous delivery occurred at 41 weeks' of gestation. Apgar scores were 9 and 10 at one and five minutes, respectively. Birth weight was 2770 g (>3rd centile), length 48 cm (3rd centile), and head circumference 30 cm (<3rd centile). A CT scan at birth showed microcephaly without any brain anomalies; the results of cerebral and renal echography were also normal. During the early neonatal period the child had feeding problems and her growth was retarded despite artificial feeding. She experienced her first febrile seizure at the age of 11 months, which was followed by a further five episodes with hyperpyrexia over the next five years. Antiepileptic therapy with phenobarbital was unsuccessful and at 6 years of age she was started on carbamazepine. She began sitting with support at the age of 2 years, but never started walking or talking. At the age of 3 years, the proband developed acute lymphoblastic leukaemia and underwent chemotherapy until remission. Echography of the heart and abdomen and laboratory examinations were normal. At 3 and 5 years, CT scans detected slight dilatation of the lateral ventricles at the level of the temporal horns and a moderate enlargement of the cortical sulci. On two subsequent occasions, EEG showed slow background activity during waking EEG recordings. When examined at the age of 5 years, her weight was 17.5 kg (10th centile), length 99 cm (<3rd centile), head circumference 42 cm (<3rd centile), and the inner and outer canthal distances were 3 cm and 8.5 cm respectively (both 75th centile). The lengths of her hand, third finger, and foot were 11 cm (<3rd centile), 4.5 cm (<3rd centile), and 14 cm (<3rd centile), respectively. Physical examination showed marked microcephaly, brachycephaly, and severe psychomotor retardation. Her facial dysmorphism included an oval-round face, a narrow forehead with a prominent metopic suture, synophrys, epicanthic folds, upward slanting palpebral fissures, hypertelorism, a short and broad nose with a flat nasal bridge, a thin, Cupid's bow shaped upper lip, normal ears with hypoplastic helices, a normal palate and short frenulum, a U shaped tongue, and no tongue protrusion. Her external genitalia were normal with mild clitoral hypertrophy. Her severe growth and mental retardation were confirmed at the age of 10 years.

Daughter 2 was delivered after 39 weeks of gestation. The pregnancy was uneventful and birth weight was 3550 g (75th centile). The results of a CT scan were normal, but cardiac echocardiography showed a ventricular septal defect that closed spontaneously. Physical examination carried out when the child was 5 years old showed that her weight was 20 kg (75th centile), height 108.5 cm (50th centile), and head circumference 55.5 cm (>97th centile). Facial dysmorphism included macrocephaly, a prominent forehead, and hypertelorism. Psychomotor and growth development was normal. The parents refused to allow publication of their children's photographs.

Cytogenetics studies were performed using PHA stimulated lymphocytes; QFQ, high resolution GTG, and RBA banded chromosomes showed a satellited chromosome 1 (1qs) in the proband (fig 1A), which was negative on CBG banding and DA-DAPI and AgNOR staining. Family investigations showed the same satellited chromosome 1 in her mother and brother, whereas her father's and sister's karyotypes were apparently normal. A satellited chromosome 15 present in the mother and inherited by the son (but not by the affected child) was thought to be a candidate partner of the translocation with chromosome 1q (fig 1B-F), and so the proband was considered monosomic for the 1qter region. The finding of the same chromosome 15 with absence of 1qs in daughter 2 suggested the presence of partial trisomy 1q. High resolution banding made it possible to define the translocation breakpoints as 1q44 and 15p12. FISH analysis was performed on lymphocytes of the mother and her two daughters using a β satellite probe (ONCOR) (fig 2). Hybridisation signals were found on 1q in the mother and syndromic child (fig 2A, B), whereas daughter 2 had the maternal translocated chromosome 15 but no signals on either chromosome 1 (fig 2C). WCP1 FISH (CAMBIO) and dual FISH analysis using 1q44-qter cosmid and 15 classical satellite probes (ONCOR) confirmed these results (fig 2D, E).

Figure 1

(A) Partial QFQ banded metaphase of the proband. The arrowhead indicates the chromosome 1qs. (B-F) Acrocentric chromosomes of the mother (B), the father (C), the first normal child (D), daughter 1 (E), and daughter 2 (F). The arrowheads indicate the chromosomes 15 carrying the 1q44-qter region instead of the chromosome satellite.

Figure 2

(A-C) FISH using β acrocentric probe. (A) The mother's chromosome 1qs is indicated by the arrow, while the arrowhead indicates the chromosome 15 with only the proximal β region hybridised. (B) Metaphase of the affected child in which all chromosomes of the D group (arrowheads) and the 1qs (arrow) show hybridisation signals. (C) Metaphase of daughter 2 with the arrowed two chromosomes 1. The maternal chromosome 15 is indicated by the arrowhead. (D-E) Dual FISH using 1q44-qter (red signal) and 15 classical satellite (green signal) probes. (D) The proband's partial metaphase showing one normal chromosome 1 (red signal), the 1qs without hybridisation signal, and two normal chromosomes 15 (green signals), corresponding to the partial 1q monosomy. (E) Daughter 2's partial metaphase showing two normal chromosomes 1 (indicated by the arrows), one chromosome 15 with double red-green signals corresponding to the partial trisomy 1q and one normal 15 chromosome (indicated by arrowheads).

Molecular analysis of the family was carried out by means of both non-radioactive and radioactive methods, using the polymorphic microsatellite markers D1S2785, D1S2842, D1S2836, and D1S2682 (fig 3). D1S2785 and D1S2842 were not involved in the rearrangement because both daughters were heterozygous for them, but the two informative distal markers (D1S2836 and D1S2682) showed that the affected child had only one allele of paternal origin, whereas daughter 2 had one paternal and one more intense maternal alleles.

Figure 3

Microsatellite analysis of the family. F: father; 1: normal son, carrier of the balanced translocation; 2: syndromic daughter 1, monosomy of chromosome 1 was evident for the microsatellite D1S2836 and D1S2682; 3: daughter 2, trisomy of chromosome 1 was deduced from the different allele intensity (D1S2836 and D1S2682); M: mother, carrier of the balanced translocation.

In brief, the mother and her first child (a son) showed the balanced translocation, whereas the karyotypes of the two daughters originated from adjacent I segregation; the first had 1q44-qter monosomy and 15p12-pter trisomy and the second had 1q44-qter trisomy and 15p12-pter monosomy. Since the gain or loss of the acrocentric short arm has no clinical significance, these sisters can be considered as having pure monosomy and pure trisomy 1q44-qter. To the best of our knowledge, there is only one published report describing monosomy involving the 1q44 distal region6; the other published deletions all involve larger regions ranging from 1q42 or 1q43 to 1qter.7-9 The 1q deletion syndrome is clinically characterised by growth and psychomotor retardation, seizures, microcephaly, brachycephaly, and typical face, hand, and foot anomalies.7-9 As the clinical features observed in our patient are the same as those described in previously reported cases, the 1q44-qter loss alone seems to be responsible for the clinical pictures of patients with distal chromosome 1q monosomy.

As far as we know, daughter 2 is the first described case of pure 1q44-qter trisomy. Previous reports have described trisomy involving the 1q42-qter region in association with monosomy of the other chromosomes.10-12 Only three patients have presented pure 1q42-qter trisomy13 14(table 1), all of whom showed growth and mental retardation, macrocephaly, a prominent forehead, and micro/retrognathia. Our patient had macrocephaly and a prominent forehead, but it is worth underlining her normal mental development at 5 years of age. This may be because of the different size of the 1q region involved and, if this is so, macrocephaly would be the only manifestation of the trisomy itself. Alternatively, the short arm of chromosome 15 may influence the expression of segment 1q44 as a result of a positional effect, but the normal phenotype allowed us to rule this out in the case of the balanced carriers of t(1;15), because it would have produced monosomy 1q44-qter caused by the lack of gene expression and consequently an abnormal phenotype. However, the absence of other published cases with pure trisomy 1q44-qter does not allow us to draw any definite conclusions. A possible mechanism generating 1q/acrocentric chromosome translocation could be an interchange between the 5S rRNA genes mapped to bands 1q42-q43 and the 18S-28S rRNA genes localised on the p arms of acrocentric chromosomes15; such a mechanism has been described in Robertsonian translocations.16 We would finally like to stress the importance of identifying both of the chromosomes involved in the translocation. The clinical picture of the affected child was suggestive of 1q deletion syndrome but, without the cytogenetic and FISH analysis of the translocation, it would have been impossible to identify the trisomic child.

Table 1

Clinical findings of the trisomic patient compared with published case reports