Pediatrics and Neonatology (2011) 52, 287e289
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Siblings With Deletion 22q13.3 and Trisomy 15q26 Inherited From a Maternally Balanced Translocation Pen-Hua Su a,b, Jia-Yuh Chen a,b,*, Suh-Jen Chen a a b
Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan Department of Pediatrics, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Received Feb 24, 2010; received in revised form Aug 24, 2010; accepted Sep 28, 2010
Key Words accelerated growth; deletion 22q; duplication 15q
We describe two siblings with generalized hypotonia, expressive language delay, developmental delay, mild facial dysmorphism, and accelerated growth. In addition, the male sibling had testis dysgenesis. Cytogenetic evaluation revealed an unbalanced maternally inherited translocation t(15;22)(q26;q13.3) resulting in partial monosomy 22q and trisomy 15q. The combination of deletion 22q and duplication 15q has not been described previously. Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction Chromosome 22 is associated with several clinically relevant cytogenetic anomalies. Cat-eye syndrome is usually associated with a chromosome 22ederived bisatellited supernumerary chromosome.1 DiGeorge syndrome or velocardiofacial syndrome is associated with a deletion or microdeletion of chromosome 22q11.2,3 Although chromosome abnormalities involving band 22q11 have been well studied, little is known about chromosome abnormalities of 22q13, the most distal band. In the literature, only
* Corresponding author. Department of Pediatrics, Chung Shan Medical University Hospital, No. 110, Section 1, Chien-Kuo North Road, Taichung City 402, Taiwan. E-mail address: [email protected]
seven cases with cytogenetically visible and two cryptic terminal deletions of 22q13.3 have been described. These patients demonstrated a generalized developmental delay, abnormal or accelerated growth, hypotonia, severe delays in expressive speech, and mildly dysmorphic facial features.4,5 To date, only one case of trisomy 15q26.1 has been described in the literature. The 35-year-old and profoundly mentally retarded male demonstrated multiple dysmorphic stigmata, including large dysplastic ears, short neck, mandibular prognathism, large bulbous deviated nose, large thick lips, severe kyphoscoliosis, pectus excaratum, horseshoe kidney, and crytorchidism.6 Here, we describe two siblings with an unbalanced maternally inherited translocation t(15;22)(q26.1;q13.3) resulting in partial monosomy 22q and partial trisomy 15q. This translocation has not been previously described, and
1875-9572/$36 Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.pedneo.2011.06.008
P.-H. Su et al
some obvious differences in growth rate between the genders in these cases were observed.
2. Case Report Case 1 (Proband 1) presented at 30 days of age for evaluation of hypotonia. He had a birth weight of 2750 g (10th percentile); birth length of 51 cm (50th percentile); head circumference (HC) of 34 cm (10the25th percentile); and was born after 36 weeks of gestation to a 30-year-old gravida 2, para 2 woman. His Apgar scores were 9 at 1 minute and 10 at 5 minutes. During the newborn period, he was noted to have a down-slanting palpebral fissure, bulbous nasal bridge, long philtrum, retro- and micrognathia, crumpled ears, a persistent foramen ovale, and feeding difficulties. The patient received hernioplasty because of an incarcerated inguinal hernia and testis dysgenesis. He presented with sensorineural hearing loss and developmental delay, and was rolling at 13 months, sitting at 15 months, crawling at 21 months, pulled to a stand at 24 months, and walked alone at 30 months. On physical examination at 30 months of age, his length was 92 cm (25the50th percentile), weight was 14 kg (50th percentile), and HC was 52 cm (>97th percentile). A brain magnetic resonance imaging showed a mild delay in myelination and a thin appearance of the corpus callosum. Bone age was mildly advanced to 3 years at 2 years and 7 months of age. The body height of this patient’s father was 160 cm and that of his mother was 158 cm. Case 2 (Proband 2) is the elder sister of Case 1 and presented at 2 years and 9 months of age for evaluation of developmental delay. She was born weighing 3250 g (25the50th percentile) after a 39-week gestation after cesarean delivery because of meconium stain. Fetal movements were not noted during pregnancy. In the newborn period, the patient was noted to have congenital pneumonia, feeding difficulties, and hypotonia. She presented with developmental delay and was rolling at 8 months, sitting at 9 months, crawling at 11 months, pulled to stand at 20 months, walked alone at 27 months, and babbled but did not produce any words until 42 months. On physical examination at 2 years and 9 months of age, her length was 95 cm (75the90th percentile), weight was 18 kg (>97th percentile), and HC was 51 cm (>97th percentile). She had a downslanting palpebral fissure, bulbous nose, broad nasal bridge, long philtrum, and micrognathia. Brain magnetic resonance imaging showed delayed myelination, a thin appearance of the corpus callosum, hydrocephalus, and cerebellum atrophy. The bone age was advanced to 5 years at 3 years and 9 months of age.
2.1. Cytogenetic analysis Cytogenetic analysis was performed on Probands 1 and 2 as well as their parents. The results of Giemsa-trypsin banding showed a derivative chromosome 22 suggestive of an unbalanced translocation (Figure 1B). The paternal chromosomes were normal (46, XY). A balanced translocation between the long arm of chromosome 15 and the long arm of chromosome 22 in the mother was detected (Figure 1A). The breakpoints were at 15q26.1 and 22q13.3.
Figure 1 Karyotype and ideogram of G-banding showing (A) Mother; balanced translation t(15;22)(q26.1q13.3) and (B) proband; the der(22)t(15;22)(q26.1;q13.3)mat.
3. Discussion Although abnormal rearrangement of proximal chromosome 15q is commonly seen in cases of inv dup(15), trisomy of the distal region of chromosome 15q is rare. Duplication 15q syndrome was initially described by Fujimoto et al.7 Duplication of distal 15q has now been described in at least 28 additional cases.8 The breakpoints are all mapped between bands 15q21 and 15q23, except for two families with breakpoints at 15q25 and two families with breakpoints at 15q15. The clinical phenotype includes postnatal growth deficiency and severe to profound mental retardation. However, two patients with duplication of 15q25/qter presented with only mild retardation. Most of the duplication 15q cases result from unbalanced translocations, all but one of which were the offsprings of a balanced carrier parent. Despite the fact that the second chromosome involved in the reciprocal translocation has varied, the clinical phenotype is consistent. A summary and comparison of the anomalies of patients with isolated trisomy 15q and monosomy 22q, as well as our sibling cases, are listed in Table 1.
Summary of findings.
Trisomy Case 1 Case 2 Deletion 15q26 22q13.3
Down-slanting palpebral fissure Bulbous nose Broad nasal bridge Long philtrum High-arch palate Micrognathia Heart defects Developmental delay/ mental retardation Joint defects Sensorineural hearing loss Slender fingers and toes Hypotonia Macrocephaly
þ þ þ þ þ
þ þ þ þ þ þ
þ þ þ þ
þ þ þ
þ þ þ þ
þ Z condition present; Z condition not present; Z condition present or absent.
Siblings with deletion 22q13.3 and trisomy 15q26 Patients with terminal 22q13 deletion syndrome share a number of clinical features, including severe expressive language delay, generalized hypotonia, developmental delay, and mild facial dysmorphism.4 Cytogenetically visible deletions of 22q13.3 are associated with the aforementioned common phenotypes and have the additional phenotype of abnormal or accelerated growth. Nesslinger et al4 documented seven patients who displayed abnormal or accelerated growth, three having macrocephaly, one being greater than the 95th percentile in height and one having large hands and feet. This was also seen in some of the cases published previously.9e11 This is unusual because most deletion syndromes and most duplication syndromes described are noted for growth retardation.12 These previously reported cases were all younger than 5 years, and no significant difference between genders was noted. It is interesting that in our cases, the female patient had accelerated growth with macrocephaly and had been greater than the 97th percentile for weight and the 90th percentile for height since the age of 2 years, and her bone age was significantly advanced by the age of 3 years. On the other hand, the male patient had normal growth for HC, height, and weight, and his bone age was only mildly advanced by the age of 2 years and 6 months. Because previous cases are rare and little is known about gender differences, differences in phenotype may become clearer over time. Overall, most patients with 22q13.3 deletion syndrome have a pure 22q deletion, either terminal or interstitial, with about 25% having deletions resulting from an unbalanced translocation or other structural rearrangement.13 SHANK 3 is the best candidate gene that might be responsible for the neurological deficits, developmental delay, and absence of speech seen in cases of 22q13.3 syndrome, because it is located in the critical region, encodes a structural protein located in the postsynaptic density, and is involved in spine maintenance of hippocampal neurons.14,15 Therefore, it may play a role in neonatal hypotonia, delayed speech, and global developmental delay, but may or may not be involved in the observed accelerated growth. In summary, we have described two unbalanced sibling patients with monosomy 22q (deletion 22q13.3 syndrome) and trisomy 15q (distal 15q trisomy) inherited from their mother who has a balanced translocation. Over the 8 years of follow-up, they demonstrated a shared combined phenotype resulting from the unbalanced translocation but displayed a difference in accelerated growth rates.
References 1. McDermid HE, Duncan AMV, Brasch CR, et al. Characterization of the supernumerary chromosome in cat eye syndrome. Science 1986;232:646e8. 2. Scambler PJ, Carey AH, Wyse RK, et al. Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome. Genomics 1991;10:201e6. 3. Driscoll DA, Spinner NB, Budarf ML, et al. Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 1992;44:261e8. 4. Nesslinger NJ, Gorski JL, Kurczynski TW, et al. Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. Am J Hum Genet 1994;54: 464e72. 5. Doheny KF, McDermid HE, Harum K, Thomas GH, Raymond GV. Cryptic terminal rearrangement of chromosome 22q13.32 detected by FISH in two unrelated patients. J Med Genet 1997; 34:640e4. 6. Baldinger S, Arthur DC, Pierpont MEM. Long-term survival in distal 15q trisomy. Am J Hum Genet 1984;36:85S. 7. Fujimoto A, Towner JW, Ebbin AJ, Kahlstrom EJ, Wilson NG. Inherited partial duplication of chromosome 15. J Med Genet 1974;11:287e91. 8. Jones KL. Duplication 15q syndrome. In: Jones KL, editor. Smith’s recognizable patterns of human malformation. 6th ed. Philadelphia, PA: Elsevier Saunders; 2006. p. 58e9. 9. Romain DR, Goldsmith J, Cairney H, Columbano-Green LM, Smythe RH, Parfitt RG. Partial monosomy for chromosome 22 in a patient with del(22)(pter-q13.3::q13.33-qter). J Med Genet 1990;27:588e9. 10. Herman GE, Greenberg F, Ledbetter DH. Multiple congenital anomaly/mental retardation (MCA/MR) syndrome with Goldehar complex due to a terminal del(22q). Am J Med Genet 1988;29:909e15. 11. Narahara K, Takahashi Y, Murakami M, et al. Terminal 22q deletion associated with a partial deficiency of arylsulfatase A. J Med Genet 1992;29:432e3. 12. Epstein CJ. The consequences of chromosome imbalanceprinciples, mechanisms, and models. Cambridge, UK: Cambridge University Press; 1986. 13. Wilson HL, Wong AC, Shaw SR, et al. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet 2003;40:575e84. 14. Bonaglia MC, Giorda R, Main E, et al. Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. J Med Genet 2006;43:822e8. 15. Roussignol G, Ango F, Romorini S, et al. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J Neurosci 2005;25:3560e70.