RESEARCH LETTER
Deletion of Chromosome 8q22.1, A Critical Region for Nablus Mask-Like Facial Syndrome: Four Additional Cases Support a Role of Genetic Modifiers in the Manifestation of the Phenotype Saumya S. Jamuar,1,2* Hatice Duzkale,1,3 Neslihan Duzkale,4 Chengsheng Zhang,1 Frances A. High,1 Leonard Kaban,5 Soma Bhattacharya,6 Barbara Crandall,7 Sibel Kantarci,7 Joan M. Stoler,8 and Angela E. Lin9 1
Harvard Medical School Genetics Training Program, Boston, Massachussetts
2
Department of Paediatric Medicine, KK Women’s and Children’s Hospital, Singapore Department of Medical Genetics, Yeditepe University School of Medicine, Istanbul, Turkey
3 4
Department of Medical Genetics, Osmangazi University School of Medicine, Eskisehir, Turkey
5
Department of Oral Maxillofacial Surgery, Massachusetts General Hospital, Boston, Massachussetts Department of Anesthesia, Massachusetts General Hospital, Boston, Massachussetts
6 7
David Geffen School of Medicine at UCLA, Los Angeles, California
8
Division of Genetics, Boston Children’s Hospital, Boston, Massachussets Genetics Unit, MassGeneral Hospital for Children, Boston, Massachussets
9
Manuscript Received: 31 March 2014; Manuscript Accepted: 26 September 2014
TO THE EDITOR: The Nablus mask-like facial syndrome (NMLFS) is a rare microdeletion syndrome with a distinctive craniofacial appearance consisting of tight-appearing glistening facial skin, blepharophimosis, telecanthus, sparse arched eyebrows, flat and broad nose, long philtrum, distinctive ears, upswept frontal hairline, short and broad neck, and developmental delay (OMIM: 608156) [Shieh et al., 2006; Raas-Rothschild et al., 2009]. We read with great interest the articles by Allanson et al. [2012] suggesting that deletion of chromosome 8q22.1 is necessary, but not sufficient for development of NMLFS, supplemented by additional patients reported by Debost-Legrand et al. [2013] and Overhoff et al. [2014], which provide further refinement of the critical region. We report on four additional patients with deletion of chromosome 8q22.1, two of whom had characteristic clinical features of NMLFS while the others did not (Table I). The comparative assessment of genomic copy deletions of these patients further supports a potential role of unidentified genetic variant(s) and/or modifier(s) in addition to the deletion of chromosome 8q22.1 in the manifestation of the full NMLFS phenotype. Patient 1 (Fig. 1) is a 14-year-old boy who was born prematurely at 35 weeks to a healthy nonconsanguineous couple of European descent. The pregnancy was complicated by polyhydramnios. Family history was unremarkable. His birth weight was 2440 g (60th centile for gestational age). At birth, he had severe micrognathia, ankylosis of the temporomandibular joint, blepharophimosis and external ear
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Jamuar SS, Duzkale H, Duzkale N, Zhang C, High FA, Kaban L, Bhattacharya S, Crandall B, Kantarci S, Stoler JM, Lin AE. 2015. Deletion of chromosome 8q22.1, a critical region for nablus mask-like facial syndrome: four additional cases support a role of genetic modifiers in the manifestation of the phenotype. Am J Med Genet Part A 167A:1400–1405.
anomalies, and required tracheostomy and gastrostomy placement in the neonatal period. His medical problems included bilateral conductive hearing loss, cryptorchidism, bilateral inguinal hernias,
Conflict of interest: none. Correspondence to: Saumya S. Jamuar, MBBS, Department of Paediatric Medicine, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 2 April 2015 DOI 10.1002/ajmg.a.36848
1400
Yes Yes
No No
NA NA
NA NA
No No
Yes No
No No
No No
TOTAL n¼ 13 (%) 3/13 (23%) 1/13 (8%) 3/12 (25%) 0/12 (0%) 4/13 (31%) 0/9 (0%) 1/13 (8%) 4/13 (31%) 3/13 (23%) 4/13 (31%) 2/9 (22%) 2/12 (17%) 0/7 (0%) 2/6 (33%) 3/12 (25%) 0/2 (0%) 1/11 (9%) 1/7 (14%) 3/7 (43%) 4/9 (44%) 4/12 (33%) 2/11 (18%) 3/11 (27%) 12/13 (92%)
NA NA
No No
Pt 4 Female þ NA þ þ
Yes Yes
Pt 3 Female þ þ þ NA þ
NA NA
TOTAL n¼10 (%) 8/10 (80%) 10/10 (100%) 8/8 (100%) 7/8 (88%) 9/10 (90%) 7/9 (77%) 10/10 (100%) 9/9 (100%) 6/8 (75%) 7/10 (70%) 3/10 (30%) 1/10 (10%) 4/7 (57%) 7/7 (100%) 6/8 (75%) 4/8 (50%) 5/8 (63%) 2/8 (25%) 0/10 (0%) 1/10 (10%) 5/9 (56%) 1/10 (10%) 6/8 (75%) 7/9 (77%)
Literatureb (n¼11) Male (6), Female (5) 2/11 1/11 2/10 0/10 4/11 0/7 1/11 4/11 3/11 4/11 1/7 1/10 0/5 2/6 3/10 NA 1/9 1/5 3/5 4/7 4/10 1/9 2/9 11/11
Pt 2 Male þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
Pt 1 Male þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
Literaturea (n¼8) Male (6), Female (2) 6/8 8/8 6/6 6/6 7/8 5/7 8/8 7/7 4/6 5/8 2/8 1/8 2/5 5/5 5/6 2/8 4/6 2/6 0/8 0/8 4/7 0/8 5/5 6/7
Pt, Patient; NA, Not available. a aShieh et al., 2006 (n ¼ 2); Barber et al., 2008 (n ¼ 2); Raas-Rothschild et al., 2009 (n ¼ 2); Overhoff et al., 2014 (n ¼ 2). b bJain et al., 2010 (n ¼ 1); Allanson et al., 2012 (n ¼ 9); Debost-Legrand et al., 2013 (n ¼ 1).
Features Sex Tight/thick facial skin Blepharophimosis Telecanthus Reduced facial movement Arched/ sparse eyebrows Frontal upsweep Pinna anomaly Bulbous nose Long philtrum Micrognathia Cleft palate: Overt or submucous Cleft lip Wide-spaced nipples Cryptorchidism Genital anomaly Inguinal hernia Contractures Increased inter-digital webbing Small hands/feet Heart defect Postnatal microcephaly Hearing loss Happy disposition Intellectual disability/ Developmental delay OPERATIONS Cleft palate repair Orthognathic surgery PROCEDURES Gastrostomy Tracheostomy
Patients with 8q22.1 deletions and without NMFLS phenotype
Patients with 8q22.1 deletions and NMLFS phenotype
TABLE I. Comparison of Features Seen in Patients With 8q22.1 Deletions With and Without the NMLFS Phenotype
JAMUAR ET AL. 1401
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. Phenotypic features of Patient 1. A, B: Patient 1 at age 14 years prior to curvilinear distraction osteogenesis. C, D, E: Patient 1 at age 14 years post curvilinear distraction osteogenesis with improvement of his micrognathia. Patient 1 shows the typical NMLFS facial features: tight appearing glistening facial skin, bilateral blepharophimosis, short downslanting palpebral fissures, sparse lateral eyebrows and eyelashes, low upswept anterior hairline, wide and depressed nasal bridge, low-set ears with dysplastic pinnae.
bronchomalacia, bronchiectasis, reactive airway disease, swallowing dysfunction and gastroesophageal reflux. Ultrasound of the head and kidneys, and echocardiogram were normal. On examination at 14 years of age, he was small for age (height 129 cm and weight 31 kg, both
Deletion of Chromosome 8q22.1, A Critical Region for Nablus Mask-Like Facial Syndrome: Four Additional Cases Support a Role of Genetic Modifiers in the Manifestation of the Phenotype Saumya S. Jamuar,1,2* Hatice Duzkale,1,3 Neslihan Duzkale,4 Chengsheng Zhang,1 Frances A. High,1 Leonard Kaban,5 Soma Bhattacharya,6 Barbara Crandall,7 Sibel Kantarci,7 Joan M. Stoler,8 and Angela E. Lin9 1
Harvard Medical School Genetics Training Program, Boston, Massachussetts
2
Department of Paediatric Medicine, KK Women’s and Children’s Hospital, Singapore Department of Medical Genetics, Yeditepe University School of Medicine, Istanbul, Turkey
3 4
Department of Medical Genetics, Osmangazi University School of Medicine, Eskisehir, Turkey
5
Department of Oral Maxillofacial Surgery, Massachusetts General Hospital, Boston, Massachussetts Department of Anesthesia, Massachusetts General Hospital, Boston, Massachussetts
6 7
David Geffen School of Medicine at UCLA, Los Angeles, California
8
Division of Genetics, Boston Children’s Hospital, Boston, Massachussets Genetics Unit, MassGeneral Hospital for Children, Boston, Massachussets
9
Manuscript Received: 31 March 2014; Manuscript Accepted: 26 September 2014
TO THE EDITOR: The Nablus mask-like facial syndrome (NMLFS) is a rare microdeletion syndrome with a distinctive craniofacial appearance consisting of tight-appearing glistening facial skin, blepharophimosis, telecanthus, sparse arched eyebrows, flat and broad nose, long philtrum, distinctive ears, upswept frontal hairline, short and broad neck, and developmental delay (OMIM: 608156) [Shieh et al., 2006; Raas-Rothschild et al., 2009]. We read with great interest the articles by Allanson et al. [2012] suggesting that deletion of chromosome 8q22.1 is necessary, but not sufficient for development of NMLFS, supplemented by additional patients reported by Debost-Legrand et al. [2013] and Overhoff et al. [2014], which provide further refinement of the critical region. We report on four additional patients with deletion of chromosome 8q22.1, two of whom had characteristic clinical features of NMLFS while the others did not (Table I). The comparative assessment of genomic copy deletions of these patients further supports a potential role of unidentified genetic variant(s) and/or modifier(s) in addition to the deletion of chromosome 8q22.1 in the manifestation of the full NMLFS phenotype. Patient 1 (Fig. 1) is a 14-year-old boy who was born prematurely at 35 weeks to a healthy nonconsanguineous couple of European descent. The pregnancy was complicated by polyhydramnios. Family history was unremarkable. His birth weight was 2440 g (60th centile for gestational age). At birth, he had severe micrognathia, ankylosis of the temporomandibular joint, blepharophimosis and external ear
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Jamuar SS, Duzkale H, Duzkale N, Zhang C, High FA, Kaban L, Bhattacharya S, Crandall B, Kantarci S, Stoler JM, Lin AE. 2015. Deletion of chromosome 8q22.1, a critical region for nablus mask-like facial syndrome: four additional cases support a role of genetic modifiers in the manifestation of the phenotype. Am J Med Genet Part A 167A:1400–1405.
anomalies, and required tracheostomy and gastrostomy placement in the neonatal period. His medical problems included bilateral conductive hearing loss, cryptorchidism, bilateral inguinal hernias,
Conflict of interest: none. Correspondence to: Saumya S. Jamuar, MBBS, Department of Paediatric Medicine, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 2 April 2015 DOI 10.1002/ajmg.a.36848
1400
Yes Yes
No No
NA NA
NA NA
No No
Yes No
No No
No No
TOTAL n¼ 13 (%) 3/13 (23%) 1/13 (8%) 3/12 (25%) 0/12 (0%) 4/13 (31%) 0/9 (0%) 1/13 (8%) 4/13 (31%) 3/13 (23%) 4/13 (31%) 2/9 (22%) 2/12 (17%) 0/7 (0%) 2/6 (33%) 3/12 (25%) 0/2 (0%) 1/11 (9%) 1/7 (14%) 3/7 (43%) 4/9 (44%) 4/12 (33%) 2/11 (18%) 3/11 (27%) 12/13 (92%)
NA NA
No No
Pt 4 Female þ NA þ þ
Yes Yes
Pt 3 Female þ þ þ NA þ
NA NA
TOTAL n¼10 (%) 8/10 (80%) 10/10 (100%) 8/8 (100%) 7/8 (88%) 9/10 (90%) 7/9 (77%) 10/10 (100%) 9/9 (100%) 6/8 (75%) 7/10 (70%) 3/10 (30%) 1/10 (10%) 4/7 (57%) 7/7 (100%) 6/8 (75%) 4/8 (50%) 5/8 (63%) 2/8 (25%) 0/10 (0%) 1/10 (10%) 5/9 (56%) 1/10 (10%) 6/8 (75%) 7/9 (77%)
Literatureb (n¼11) Male (6), Female (5) 2/11 1/11 2/10 0/10 4/11 0/7 1/11 4/11 3/11 4/11 1/7 1/10 0/5 2/6 3/10 NA 1/9 1/5 3/5 4/7 4/10 1/9 2/9 11/11
Pt 2 Male þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
Pt 1 Male þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
Literaturea (n¼8) Male (6), Female (2) 6/8 8/8 6/6 6/6 7/8 5/7 8/8 7/7 4/6 5/8 2/8 1/8 2/5 5/5 5/6 2/8 4/6 2/6 0/8 0/8 4/7 0/8 5/5 6/7
Pt, Patient; NA, Not available. a aShieh et al., 2006 (n ¼ 2); Barber et al., 2008 (n ¼ 2); Raas-Rothschild et al., 2009 (n ¼ 2); Overhoff et al., 2014 (n ¼ 2). b bJain et al., 2010 (n ¼ 1); Allanson et al., 2012 (n ¼ 9); Debost-Legrand et al., 2013 (n ¼ 1).
Features Sex Tight/thick facial skin Blepharophimosis Telecanthus Reduced facial movement Arched/ sparse eyebrows Frontal upsweep Pinna anomaly Bulbous nose Long philtrum Micrognathia Cleft palate: Overt or submucous Cleft lip Wide-spaced nipples Cryptorchidism Genital anomaly Inguinal hernia Contractures Increased inter-digital webbing Small hands/feet Heart defect Postnatal microcephaly Hearing loss Happy disposition Intellectual disability/ Developmental delay OPERATIONS Cleft palate repair Orthognathic surgery PROCEDURES Gastrostomy Tracheostomy
Patients with 8q22.1 deletions and without NMFLS phenotype
Patients with 8q22.1 deletions and NMLFS phenotype
TABLE I. Comparison of Features Seen in Patients With 8q22.1 Deletions With and Without the NMLFS Phenotype
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1402
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. Phenotypic features of Patient 1. A, B: Patient 1 at age 14 years prior to curvilinear distraction osteogenesis. C, D, E: Patient 1 at age 14 years post curvilinear distraction osteogenesis with improvement of his micrognathia. Patient 1 shows the typical NMLFS facial features: tight appearing glistening facial skin, bilateral blepharophimosis, short downslanting palpebral fissures, sparse lateral eyebrows and eyelashes, low upswept anterior hairline, wide and depressed nasal bridge, low-set ears with dysplastic pinnae.
bronchomalacia, bronchiectasis, reactive airway disease, swallowing dysfunction and gastroesophageal reflux. Ultrasound of the head and kidneys, and echocardiogram were normal. On examination at 14 years of age, he was small for age (height 129 cm and weight 31 kg, both
