122 Short case report
Bilateral absence of the ulna in 4q terminal deletion syndrome: evidence for a critical region Tyson Meauxa, Amy Zeringueb, Christy Mumphreyb, Brian Barkemeyerb and Michael Marblec Clinical Dysmorphology 2015, 24:122–124 a
Louisiana State University Health Sciences Center, School of Medicine, Department of Pediatrics, Louisiana State University Health Sciences Center, Division of Neonatology and cDepartment of Pediatrics, Louisiana State University Health Sciences Center, Division of Clinical Genetics, Children’s Hospital of New Orleans, New Orleans, Louisiana, USA b
List of key features 4q terminal deletion Absent ulna Micrognathia Cleft palate Single digit on hands
Case report The patient reported here was born at 38 weeks gestation by spontaneous vaginal delivery. The pregnancy was complicated by intrauterine growth retardation, oligohydramnios, maternal hepatitis C, and suspected cocaine use. Birth weight was 3000 g. The patient had slightly upslanting palpebral fissures, inner epicanthal folds, arched eyebrows, a long smooth philtrum, cleft palate, and micrognathia (Fig. 1). The arms were short and the forearms were severely hypoplastic with a single digit bilaterally (Fig. 1). Other limb anomalies included elbow contractures with webbing, and slight overlap of the second and third toes. Skeletal survey showed short humeri and absent ulnae bilaterally. In the single digit, there was a hypoplastic metacarpal, small welldeveloped proximal and distal phalanges, but apparent absence of the mid phalanx (Fig. 2). Echocardiogram showed atrial septal defect and small patent ductus arteriosus. At 8 months of age, length was 65 cm (5th percentile), weight 7 kg (10th–25th percentile), and head circumference was 43.4 cm (50th percentile). As of 9 months of age the patient held a sitting position, cooed and babbled but did not yet crawl. At 2 years of age, weight was 10.6 kg (10th– 25th percentile) and length was 80 cm (5th percentile). She said ∼ 15 words but no sentences. She sat on her own and pulled up on furniture but did not walk. The atrial septal defect and patent ductus arteriosus closed spontaneously. She was treated with ranitidine for gastroesophageal reflux. Consent for publication of clinical photos and patient information was obtained. Investigations
Chromosome microarray analysis showed a 21.98 Mbp deletion at 4q32.3–4qter, with genomic coordinates 4 : 169,154,141–191,133,858. Within this region are 39
Correspondence to Michael Marble, MD, Department of Pediatrics, Louisiana State University Health Sciences Center, Division of Clinical Genetics, Children’s Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA 70118, USA Tel: + 1 504 896 9254; fax: + 1 504 896 3997; e-mail: [email protected] Received 1 October 2014 Accepted 19 January 2015
genes listed in OMIM and 51 other genes. None of the genes in the region are associated with any known syndromes. Additionally, there was a heterozygous 296.72 kbp deletion detected at 8q12.1 within the IMPAD1 locus. Homozygous mutations in IMPAD1 are associated with chondrodysplasia with joint dislocations (GRAPP type) (Vissers et al., 2011) and have also been reported in two patients with phenotypes similar to Catel–Manzke syndrome (Nizon et al. 2012). The IMPAD1 deletion in our patient was heterozygous and therefore of no apparent clinical significance. Fig. 1
Facial features and upper limbs of proband at 9 months of age. Note arched eyebrows, inner epicanthal folds, upslanting palpebral fissures, long philtrum, and micrognathia. The forearms are hypoplastic and terminate into a single digit bilaterally.
0962-8827 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MCD.0000000000000078
4q terminal deletion with absent ulnae Meaux et al. 123
Menko et al., 1992). In the case of Menko et al. (1992) there was complete absence of the left ulna. Subsequently, Keeling et al. (2001) reported a patient with absent left ulna associated with interstitial deletion at 4q32–34 and proposed that genes for distal arm development (particularly the left ulnar ray) reside at 4q33. Genomic coordinates of the deletion were not provided in that article. The above reports suggest an association of 4q deletions with ulnar ray defects; however genotype–phenotype correlations are limited due to sparse molecular data.
Fig. 2
Radiograph showing absent left ulna with single digit. The metacarpal appears hypoplastic and the middle phalange is absent.
Discussion Phenotypic features associated with terminal 4q deletions are quite variable. Vona et al. (2014) proposed critical regions for some of the more common findings including cleft palate, congenital heart defects, autism spectrum disorder, and intellectual disability. The patient in our report was born with cleft palate and a congenital heart defect and her deletion encompassed the proposed critical regions for these anomalies. In addition, she has developmental delay and her deletion included the proposed critical region for intellectual disability. Therefore, genotype–phenotype correlation in our patient is consistent with the critical regions proposed by Vona et al. (2014). However, a critical region for the absent ulna has not been delineated on a molecular basis (Vona et al., 2014). In the current report, we review other cases of absent ulna in the terminal 4q deletion syndrome, characterized on a molecular basis, and attempt to delineate a consistent chromosomal region for this anomaly. Before the era of chromosome microarray there were several reports of cytogenetically detected deletions involving 4q in patients with ulnar ray deficiencies (Tomkins et al., 1982; Lin et al., 1988; Tejada et al., 1990;
Kaalund et al. (2008) reported a patient with 4q deletion who, like our patient, had bilateral absence of the ulna. Three ulnar digital rays were absent on the left hand, and all four ulnar digital rays were absent on the right. The deletion coordinates were 4 : 171,230,000-qter. The patient also had a 4.5 Mbp terminal duplication at 20p and a 1 Mbp duplication at 2q which may also contribute to the patient’s overall phenotype. Strehle et al. (2012) reviewed 20 patients with 4q deletion analyzed by chromosome microarray. Of those patients, 10 had deletions overlapping that of our patient. Patient 13 in their report had an absent left ulna and absent left third, fourth, and fifth fingers. Deletion coordinates were 4 : 164,074,495–188,987,971. The common segment of overlap between the deletion of our patient and the deletions of Strehle et al. (2012) (patient 13) and Kaalund et al. (2008) is 4 : 171,230,000–188,987,971. Thus, it is likely that the occurrence of absent ulna in 4q terminal deletion syndrome is due to haploinsufficiency of a gene or genes within these coordinates. Several other patients in the report by Strehle et al. (2012) had 4q deletions overlapping that of our patient and had variable limb anomalies including ulnar digital ray deficiencies. However, absent ulna was not listed as a feature in those patients. Thus, as with other aspects of the 4q terminal deletion phenotype, there appears to be variable clinical expressivity and penetrance of ulnar ray anomalies. Our report supports the proposal by Keeling et al. (2001) that genes in the terminal 4q region play a role in distal arm development. Moreover, comparison of the genomic coordinates in our study with that of previous reports helps define a consistent region for ulnar defects which encompasses the genomic coordinates 4 : 171,230,000– 188,987,971. Additional reports are needed to further narrow the critical region for ulnar defects in the 4q terminal deletion syndrome.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
124 Clinical Dysmorphology
2015, Vol 24 No 3
References Kaalund SS, Møller RS, Tészás A, Miranda M, Kosztolanyi G, Ullmann R, et al. (2008). Investigation of 4q-deletion in two unrelated patients using array CGH. Am J Med Genet A 146A:2431–2434. Keeling SL, Lee-Jones L, Thompson P (2001). Interstitial deletion 4q32-34 with ulnar deficiency: 4q33 may be the critical region in 4q terminal deletion syndrome. Am J Med Genet 99:94–98. Lin AE, Garver KL, Diggans G, Clemens M, Wenger SL, Steele MW, et al. (1988). Interstitial and terminal deletions of the long arm of chromosome 4: further delineation of phenotypes. Am J Med Genet 31:533–548. Menko FH, Madan K, Baart JA, Beukenhorst HL (1992). Robin sequence and a deficiency of the left forearm in a girl with a deletion of chromosome 4q33-qter. Am J Med Genet 44:696–698. Nizon M, Alanay Y, Tuysuz B, Kiper PO, Genevieve D, Sillence D, et al. (2012). IMPAD1 mutations in two Catel–Manzke like patients. Am J Med Genet A 158A:2183–2187.
Strehle EM, Yu L, Rosenfeld JA, Donkervoort S, Zhou Y, Chen TJ, et al. (2012). Genotype–phenotype analysis of 4q deletion syndrome: proposal of a critical region. Am J Med Genet A 158A:2139–2151. Tejada MI, Mendoza R, Carbonero K, Lizarraga MA, Escudero F, Benito JA (1990). Deletion of chromosome 4: 46 XY, del(4)(q31.1) after gamete intrafallopian transfer and in vitro fertilization-embryo transfer. Fertil Steril 54:953–954. Tomkins DJ, Hunter AG, Uchida IA, Roberts MH (1982). Two children with deletion of the long arm of chromosome 4 with breakpoint at band q33. Clin Genet 22:348–355. Vissers LE, Lausch E, Unger S, Campos-Xavier AB, Gilissen C, Rossi A, et al. (2011). Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP. Am J Hum Genet 88:608–615. Vona B, Nanda I, Neuner C, Schroder J, Kalscheuer VM, Shehata-Dieler W, Haaf T (2014). Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature. BMC Med Genet 15:72.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Bilateral absence of the ulna in 4q terminal deletion syndrome: evidence for a critical region Tyson Meauxa, Amy Zeringueb, Christy Mumphreyb, Brian Barkemeyerb and Michael Marblec Clinical Dysmorphology 2015, 24:122–124 a
Louisiana State University Health Sciences Center, School of Medicine, Department of Pediatrics, Louisiana State University Health Sciences Center, Division of Neonatology and cDepartment of Pediatrics, Louisiana State University Health Sciences Center, Division of Clinical Genetics, Children’s Hospital of New Orleans, New Orleans, Louisiana, USA b
List of key features 4q terminal deletion Absent ulna Micrognathia Cleft palate Single digit on hands
Case report The patient reported here was born at 38 weeks gestation by spontaneous vaginal delivery. The pregnancy was complicated by intrauterine growth retardation, oligohydramnios, maternal hepatitis C, and suspected cocaine use. Birth weight was 3000 g. The patient had slightly upslanting palpebral fissures, inner epicanthal folds, arched eyebrows, a long smooth philtrum, cleft palate, and micrognathia (Fig. 1). The arms were short and the forearms were severely hypoplastic with a single digit bilaterally (Fig. 1). Other limb anomalies included elbow contractures with webbing, and slight overlap of the second and third toes. Skeletal survey showed short humeri and absent ulnae bilaterally. In the single digit, there was a hypoplastic metacarpal, small welldeveloped proximal and distal phalanges, but apparent absence of the mid phalanx (Fig. 2). Echocardiogram showed atrial septal defect and small patent ductus arteriosus. At 8 months of age, length was 65 cm (5th percentile), weight 7 kg (10th–25th percentile), and head circumference was 43.4 cm (50th percentile). As of 9 months of age the patient held a sitting position, cooed and babbled but did not yet crawl. At 2 years of age, weight was 10.6 kg (10th– 25th percentile) and length was 80 cm (5th percentile). She said ∼ 15 words but no sentences. She sat on her own and pulled up on furniture but did not walk. The atrial septal defect and patent ductus arteriosus closed spontaneously. She was treated with ranitidine for gastroesophageal reflux. Consent for publication of clinical photos and patient information was obtained. Investigations
Chromosome microarray analysis showed a 21.98 Mbp deletion at 4q32.3–4qter, with genomic coordinates 4 : 169,154,141–191,133,858. Within this region are 39
Correspondence to Michael Marble, MD, Department of Pediatrics, Louisiana State University Health Sciences Center, Division of Clinical Genetics, Children’s Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA 70118, USA Tel: + 1 504 896 9254; fax: + 1 504 896 3997; e-mail: [email protected] Received 1 October 2014 Accepted 19 January 2015
genes listed in OMIM and 51 other genes. None of the genes in the region are associated with any known syndromes. Additionally, there was a heterozygous 296.72 kbp deletion detected at 8q12.1 within the IMPAD1 locus. Homozygous mutations in IMPAD1 are associated with chondrodysplasia with joint dislocations (GRAPP type) (Vissers et al., 2011) and have also been reported in two patients with phenotypes similar to Catel–Manzke syndrome (Nizon et al. 2012). The IMPAD1 deletion in our patient was heterozygous and therefore of no apparent clinical significance. Fig. 1
Facial features and upper limbs of proband at 9 months of age. Note arched eyebrows, inner epicanthal folds, upslanting palpebral fissures, long philtrum, and micrognathia. The forearms are hypoplastic and terminate into a single digit bilaterally.
0962-8827 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MCD.0000000000000078
4q terminal deletion with absent ulnae Meaux et al. 123
Menko et al., 1992). In the case of Menko et al. (1992) there was complete absence of the left ulna. Subsequently, Keeling et al. (2001) reported a patient with absent left ulna associated with interstitial deletion at 4q32–34 and proposed that genes for distal arm development (particularly the left ulnar ray) reside at 4q33. Genomic coordinates of the deletion were not provided in that article. The above reports suggest an association of 4q deletions with ulnar ray defects; however genotype–phenotype correlations are limited due to sparse molecular data.
Fig. 2
Radiograph showing absent left ulna with single digit. The metacarpal appears hypoplastic and the middle phalange is absent.
Discussion Phenotypic features associated with terminal 4q deletions are quite variable. Vona et al. (2014) proposed critical regions for some of the more common findings including cleft palate, congenital heart defects, autism spectrum disorder, and intellectual disability. The patient in our report was born with cleft palate and a congenital heart defect and her deletion encompassed the proposed critical regions for these anomalies. In addition, she has developmental delay and her deletion included the proposed critical region for intellectual disability. Therefore, genotype–phenotype correlation in our patient is consistent with the critical regions proposed by Vona et al. (2014). However, a critical region for the absent ulna has not been delineated on a molecular basis (Vona et al., 2014). In the current report, we review other cases of absent ulna in the terminal 4q deletion syndrome, characterized on a molecular basis, and attempt to delineate a consistent chromosomal region for this anomaly. Before the era of chromosome microarray there were several reports of cytogenetically detected deletions involving 4q in patients with ulnar ray deficiencies (Tomkins et al., 1982; Lin et al., 1988; Tejada et al., 1990;
Kaalund et al. (2008) reported a patient with 4q deletion who, like our patient, had bilateral absence of the ulna. Three ulnar digital rays were absent on the left hand, and all four ulnar digital rays were absent on the right. The deletion coordinates were 4 : 171,230,000-qter. The patient also had a 4.5 Mbp terminal duplication at 20p and a 1 Mbp duplication at 2q which may also contribute to the patient’s overall phenotype. Strehle et al. (2012) reviewed 20 patients with 4q deletion analyzed by chromosome microarray. Of those patients, 10 had deletions overlapping that of our patient. Patient 13 in their report had an absent left ulna and absent left third, fourth, and fifth fingers. Deletion coordinates were 4 : 164,074,495–188,987,971. The common segment of overlap between the deletion of our patient and the deletions of Strehle et al. (2012) (patient 13) and Kaalund et al. (2008) is 4 : 171,230,000–188,987,971. Thus, it is likely that the occurrence of absent ulna in 4q terminal deletion syndrome is due to haploinsufficiency of a gene or genes within these coordinates. Several other patients in the report by Strehle et al. (2012) had 4q deletions overlapping that of our patient and had variable limb anomalies including ulnar digital ray deficiencies. However, absent ulna was not listed as a feature in those patients. Thus, as with other aspects of the 4q terminal deletion phenotype, there appears to be variable clinical expressivity and penetrance of ulnar ray anomalies. Our report supports the proposal by Keeling et al. (2001) that genes in the terminal 4q region play a role in distal arm development. Moreover, comparison of the genomic coordinates in our study with that of previous reports helps define a consistent region for ulnar defects which encompasses the genomic coordinates 4 : 171,230,000– 188,987,971. Additional reports are needed to further narrow the critical region for ulnar defects in the 4q terminal deletion syndrome.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
124 Clinical Dysmorphology
2015, Vol 24 No 3
References Kaalund SS, Møller RS, Tészás A, Miranda M, Kosztolanyi G, Ullmann R, et al. (2008). Investigation of 4q-deletion in two unrelated patients using array CGH. Am J Med Genet A 146A:2431–2434. Keeling SL, Lee-Jones L, Thompson P (2001). Interstitial deletion 4q32-34 with ulnar deficiency: 4q33 may be the critical region in 4q terminal deletion syndrome. Am J Med Genet 99:94–98. Lin AE, Garver KL, Diggans G, Clemens M, Wenger SL, Steele MW, et al. (1988). Interstitial and terminal deletions of the long arm of chromosome 4: further delineation of phenotypes. Am J Med Genet 31:533–548. Menko FH, Madan K, Baart JA, Beukenhorst HL (1992). Robin sequence and a deficiency of the left forearm in a girl with a deletion of chromosome 4q33-qter. Am J Med Genet 44:696–698. Nizon M, Alanay Y, Tuysuz B, Kiper PO, Genevieve D, Sillence D, et al. (2012). IMPAD1 mutations in two Catel–Manzke like patients. Am J Med Genet A 158A:2183–2187.
Strehle EM, Yu L, Rosenfeld JA, Donkervoort S, Zhou Y, Chen TJ, et al. (2012). Genotype–phenotype analysis of 4q deletion syndrome: proposal of a critical region. Am J Med Genet A 158A:2139–2151. Tejada MI, Mendoza R, Carbonero K, Lizarraga MA, Escudero F, Benito JA (1990). Deletion of chromosome 4: 46 XY, del(4)(q31.1) after gamete intrafallopian transfer and in vitro fertilization-embryo transfer. Fertil Steril 54:953–954. Tomkins DJ, Hunter AG, Uchida IA, Roberts MH (1982). Two children with deletion of the long arm of chromosome 4 with breakpoint at band q33. Clin Genet 22:348–355. Vissers LE, Lausch E, Unger S, Campos-Xavier AB, Gilissen C, Rossi A, et al. (2011). Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP. Am J Hum Genet 88:608–615. Vona B, Nanda I, Neuner C, Schroder J, Kalscheuer VM, Shehata-Dieler W, Haaf T (2014). Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature. BMC Med Genet 15:72.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
