Short case report 149
Wolf–Hirschhorn syndrome: a historical note and comment on an older adult Claire J. Searlea, Emma Shearingb and Oliver W. Quarrella Clinical Dysmorphology 2013, 22:149–151 a
b
Department of Clinical Genetics and Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK
Correspondence to Claire J. Searle, MBChB, Department of Clinical Genetics, Sheffield Children’s NHS Foundation Trust, Western Bank, Sheffield, S10 2TH, UK Tel: + 44 114 2717027; fax: + 44 114 2737467; e-mail: [email protected] Received 7 June 2013 Accepted 31 July 2013
List of key features Intellectual disability Microcephaly Prominent glabella Hypertelorism Seizures
Summary The case of a family in which three affected sisters were born to healthy nonconsanguineous parents was reported in 1974 as Smith–Lemli–Opitz syndrome (Bundey and Smyth, 1974). The karyotype analysis at that time was normal. The phenotype of the sisters continued to suggest a chromosomal imbalance and hence further cytogenetic studies were undertaken. After a clinical suggestion of the diagnosis of Wolf–Hirschhorn syndrome (WHS), the chromosome analysis was repeated for a fourth time, and the family was reported again in 1991 as a case of WHS (Hill et al., 1991) with the karyotype 46,XX,-4, + der(4)t(4;22)mat. The family came to the attention of the present authors when the mother and the oldest surviving affected sibling, now aged 51 years, attended a WHS support group meeting. The youngest sister was observed to have seizures from the age of 8 months. She had a major seizure at the age of 6 years and subsequently died of bronchopneumonia. The middle sister also developed seizures at a young age, which were successfully controlled for a number of years; however, despite continuing on medication, her grand mal seizures restarted at the age of 32 years. At the age of 37 years, she was found in a postictal state from which she did not recover and died in hospital 9 days later. The oldest sister is aged 51 years and lives in a community home with 24 h supervision. She was born at 42 weeks with a birth weight of 2 kg (– 3.1 SD). She began to sit at the age of 1 year and stood with support shortly afterwards. At the age of 10 years, she walked with encouragement. She can still take a few steps with support but uses a tricycle for mobility. She is semicontinent and previously had constipation. A heart murmur was observed in childhood, but this has not required treatment. She has scoliosis and marked lumbar lordosis. Her peripheries are cold. She is microcephalic with an OFC of 44 cm and has required anticonvulsant therapy c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0962-8827
since the age of 2 months. Her facial features are shown in Figs 1–3 at the age of 18 months, 9 years and 50 years. Her general health has been good, but she recently experienced a gastrointestinal bleed. The investigation after this episode demonstrated gastritis, a tortuous oesophagus and hiatus hernia. A Helicobacter pylori infection was also confirmed. Array comparative genomic hybridization analysis using BlueGnome (Cambridge, UK) 60k ISCA oligo array and fluorescence in-situ hybridization analysis using the Vysis WHS probe confirmed a deletion of B9 Mb (Fig. 4). The updated karyotype is now reported as 46,XX,der(4)t(4;22) (p16.1;p13)mat.ish der(4)t(4;22)(WHS-).arr4p16.3p16.1(27,1529,423,849)x1.
Discussion We have been able to update information on a family that has been reported previously. There have been previous reports on adults with WHS in the literature (Smith et al., 1995; Ogle et al., 1996; Marcelis et al., 2001; Lopes et al., 2005; Coppola et al., 2013); however, this is the case of the oldest person reported to date. The previous descriptions of WHS focus mainly on the dysmorphology and health issues of cases seen in childhood. It is known that WHS patients can survive into adulthood. Shannon et al. (2001) reported Kaplan–Meier survival curves for a cohort of 132 patients of whom 36 had died. Separate curves were drawn for those with de-novo deletions and translocation, but neither reached 50%; therefore, a median survival could not be calculated, except to say that it was greater than 34 years and 18 years for each of the curves, respectively. This family was not included in the above-mentioned analysis. Apart from its historical interest, this case illustrates that seizures may become quiescent as children age (Worthington et al., 2008); however, redevelopment of grand mal seizures may also occur in adults, as was seen in case of one of the sisters in this family. Parents of newly diagnosed children ask about the prognosis, which in most cases is guarded; however, it is important to realize that some milestone may be reached after a very significant delay, for example, walking at the age of 10 years, as was seen in this case. We believe this to be the oldest reported case in the literature and publish the facial features to illustrate how DOI: 10.1097/MCD.0000000000000005
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
150
Clinical Dysmorphology 2013, Vol 22 No 4
Fig. 1
Case1: at the age of 50 years. Frontal facial view showing a wide nasal bridge, strabismus, ocular hypertelorism, long nose and appearance of a short philtrum. Left-sided lateral view showing a poorly formed ear. These images can be compared with those of childhood published by Bundey and Smyth (1974) and Hill et al. (1991).
Fig. 2 Fig. 3
At the age of 18 months. Note the broad-base nose, prominent forehead, epicanthic folds and upsweep to the eyebrows. Original images published by Bundey and Smyth (1974).
At the age of 9 years. Note the broad-base nose and unfolded ears. Original images published by Bundey and Smyth (1974).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Wolf–Hirschhorn syndrome – an update Searle et al. 151
Fig. 4 Chromosomal position
Log2 ratio Ch1/Ch2 2.00 1.60 1.20 0.80 0.40 −0.00 −0.40 −0.80 −1.20 −1.60
p16.3 3:197, 423 Kb
p16.1
15 4–
13 4–
12 4–
10 4–
9 4–
7 4–
5 4–
4 4–
2 4–
1 4–
3–
19
7
−2.00
p15.33 4:14,593 Kb
Current Disease Genes
DGV G DGV L ISCA C G ISCA C L
Array profile for the 60 K ISCA Oligo array (top) and a modified view of the BlueFuse Multi v2.3 decision tracks for the region containing the deletion (from basepairs 75677 to 9817451). The tracks shown include, from top to bottom, the deletion, disease regions, genes, DGV gain and loss data and ISCA consensus gain and loss data.
the adults age. The appearance of being prematurely aged has been commented upon previously (Battaglia et al., 2008).
Acknowledgements The authors thank the family for all their help in writing this article. Conflicts of interest
There are no conflicts of interest.
References Battaglia A, Filippi T, Carey JC (2008). Update on the clinical features and natural history of Wolf–Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision. Am J Med Genet C Semin Med Genet 148C:246–251. Bundey S, Smyth HC (1974). Three sisters with the Smith–Lemli–Opitz syndrome. J Ment Defic Res 18:51–61.
Coppola A, Chinthapalli K, Hammond P, Sander JW, Sisodiya SM (2013). Pediatric diagnosis not made until adulthood: a case of Wolf–Hirschhorn syndrome. Gene 512:532–535. Hill S, Creasy M, Bundey S (1991). A family with three sisters with the 4p- syndrome originally reported as suffering from the Smith–Lemli–Opitz syndrome. J Ment Defic Res 35:76–80. Lopes O, Barton G, Morgan J (2005). Wolf–Hirschhorn syndrome – two casestudy reports focusing particularly on long-term survival. J Intellect Disabil Res 49 (Pt 3):228–230. Marcelis C, Schrander-Stumpel C, Engelen J, Schoonbrood-Lenssen A, Willemse A, Beemer F, et al. (2001). Wolf–Hirschhorn (4p-) syndrome in adults. Genet Couns 12:35–48. Ogle R, O’Sillence DO, Merrick A, Ell J, Lo B, Robson L (1996). The Wolf–Hirschorn syndrome in adulthood: evaluation of a 24 year old man with a rec(4) chromosome. Am J Med Genet 65:124–127. Shannon NL, Maltby EL, Rigby AS, Quarrell OW (2001). An epidemiological study of Wolf–Hirschhorn syndrome: life expectancy and cause of mortality. J Med Genet 38:674–679. Smith SA, Walker AD, Monk AJ, Young ID (1995). Long term survival in the Wolf–Hirschorn (4p-) syndrome. J Ment Defic Res 39:83–86. Worthington JC, Rigby AS, Quarrell OW (2008). Seizure frequency in adults with Wolf–Hirschhorn syndrome. Am J Med Genet A 146A:2528–2531.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Wolf–Hirschhorn syndrome: a historical note and comment on an older adult Claire J. Searlea, Emma Shearingb and Oliver W. Quarrella Clinical Dysmorphology 2013, 22:149–151 a
b
Department of Clinical Genetics and Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK
Correspondence to Claire J. Searle, MBChB, Department of Clinical Genetics, Sheffield Children’s NHS Foundation Trust, Western Bank, Sheffield, S10 2TH, UK Tel: + 44 114 2717027; fax: + 44 114 2737467; e-mail: [email protected] Received 7 June 2013 Accepted 31 July 2013
List of key features Intellectual disability Microcephaly Prominent glabella Hypertelorism Seizures
Summary The case of a family in which three affected sisters were born to healthy nonconsanguineous parents was reported in 1974 as Smith–Lemli–Opitz syndrome (Bundey and Smyth, 1974). The karyotype analysis at that time was normal. The phenotype of the sisters continued to suggest a chromosomal imbalance and hence further cytogenetic studies were undertaken. After a clinical suggestion of the diagnosis of Wolf–Hirschhorn syndrome (WHS), the chromosome analysis was repeated for a fourth time, and the family was reported again in 1991 as a case of WHS (Hill et al., 1991) with the karyotype 46,XX,-4, + der(4)t(4;22)mat. The family came to the attention of the present authors when the mother and the oldest surviving affected sibling, now aged 51 years, attended a WHS support group meeting. The youngest sister was observed to have seizures from the age of 8 months. She had a major seizure at the age of 6 years and subsequently died of bronchopneumonia. The middle sister also developed seizures at a young age, which were successfully controlled for a number of years; however, despite continuing on medication, her grand mal seizures restarted at the age of 32 years. At the age of 37 years, she was found in a postictal state from which she did not recover and died in hospital 9 days later. The oldest sister is aged 51 years and lives in a community home with 24 h supervision. She was born at 42 weeks with a birth weight of 2 kg (– 3.1 SD). She began to sit at the age of 1 year and stood with support shortly afterwards. At the age of 10 years, she walked with encouragement. She can still take a few steps with support but uses a tricycle for mobility. She is semicontinent and previously had constipation. A heart murmur was observed in childhood, but this has not required treatment. She has scoliosis and marked lumbar lordosis. Her peripheries are cold. She is microcephalic with an OFC of 44 cm and has required anticonvulsant therapy c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0962-8827
since the age of 2 months. Her facial features are shown in Figs 1–3 at the age of 18 months, 9 years and 50 years. Her general health has been good, but she recently experienced a gastrointestinal bleed. The investigation after this episode demonstrated gastritis, a tortuous oesophagus and hiatus hernia. A Helicobacter pylori infection was also confirmed. Array comparative genomic hybridization analysis using BlueGnome (Cambridge, UK) 60k ISCA oligo array and fluorescence in-situ hybridization analysis using the Vysis WHS probe confirmed a deletion of B9 Mb (Fig. 4). The updated karyotype is now reported as 46,XX,der(4)t(4;22) (p16.1;p13)mat.ish der(4)t(4;22)(WHS-).arr4p16.3p16.1(27,1529,423,849)x1.
Discussion We have been able to update information on a family that has been reported previously. There have been previous reports on adults with WHS in the literature (Smith et al., 1995; Ogle et al., 1996; Marcelis et al., 2001; Lopes et al., 2005; Coppola et al., 2013); however, this is the case of the oldest person reported to date. The previous descriptions of WHS focus mainly on the dysmorphology and health issues of cases seen in childhood. It is known that WHS patients can survive into adulthood. Shannon et al. (2001) reported Kaplan–Meier survival curves for a cohort of 132 patients of whom 36 had died. Separate curves were drawn for those with de-novo deletions and translocation, but neither reached 50%; therefore, a median survival could not be calculated, except to say that it was greater than 34 years and 18 years for each of the curves, respectively. This family was not included in the above-mentioned analysis. Apart from its historical interest, this case illustrates that seizures may become quiescent as children age (Worthington et al., 2008); however, redevelopment of grand mal seizures may also occur in adults, as was seen in case of one of the sisters in this family. Parents of newly diagnosed children ask about the prognosis, which in most cases is guarded; however, it is important to realize that some milestone may be reached after a very significant delay, for example, walking at the age of 10 years, as was seen in this case. We believe this to be the oldest reported case in the literature and publish the facial features to illustrate how DOI: 10.1097/MCD.0000000000000005
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
150
Clinical Dysmorphology 2013, Vol 22 No 4
Fig. 1
Case1: at the age of 50 years. Frontal facial view showing a wide nasal bridge, strabismus, ocular hypertelorism, long nose and appearance of a short philtrum. Left-sided lateral view showing a poorly formed ear. These images can be compared with those of childhood published by Bundey and Smyth (1974) and Hill et al. (1991).
Fig. 2 Fig. 3
At the age of 18 months. Note the broad-base nose, prominent forehead, epicanthic folds and upsweep to the eyebrows. Original images published by Bundey and Smyth (1974).
At the age of 9 years. Note the broad-base nose and unfolded ears. Original images published by Bundey and Smyth (1974).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Wolf–Hirschhorn syndrome – an update Searle et al. 151
Fig. 4 Chromosomal position
Log2 ratio Ch1/Ch2 2.00 1.60 1.20 0.80 0.40 −0.00 −0.40 −0.80 −1.20 −1.60
p16.3 3:197, 423 Kb
p16.1
15 4–
13 4–
12 4–
10 4–
9 4–
7 4–
5 4–
4 4–
2 4–
1 4–
3–
19
7
−2.00
p15.33 4:14,593 Kb
Current Disease Genes
DGV G DGV L ISCA C G ISCA C L
Array profile for the 60 K ISCA Oligo array (top) and a modified view of the BlueFuse Multi v2.3 decision tracks for the region containing the deletion (from basepairs 75677 to 9817451). The tracks shown include, from top to bottom, the deletion, disease regions, genes, DGV gain and loss data and ISCA consensus gain and loss data.
the adults age. The appearance of being prematurely aged has been commented upon previously (Battaglia et al., 2008).
Acknowledgements The authors thank the family for all their help in writing this article. Conflicts of interest
There are no conflicts of interest.
References Battaglia A, Filippi T, Carey JC (2008). Update on the clinical features and natural history of Wolf–Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision. Am J Med Genet C Semin Med Genet 148C:246–251. Bundey S, Smyth HC (1974). Three sisters with the Smith–Lemli–Opitz syndrome. J Ment Defic Res 18:51–61.
Coppola A, Chinthapalli K, Hammond P, Sander JW, Sisodiya SM (2013). Pediatric diagnosis not made until adulthood: a case of Wolf–Hirschhorn syndrome. Gene 512:532–535. Hill S, Creasy M, Bundey S (1991). A family with three sisters with the 4p- syndrome originally reported as suffering from the Smith–Lemli–Opitz syndrome. J Ment Defic Res 35:76–80. Lopes O, Barton G, Morgan J (2005). Wolf–Hirschhorn syndrome – two casestudy reports focusing particularly on long-term survival. J Intellect Disabil Res 49 (Pt 3):228–230. Marcelis C, Schrander-Stumpel C, Engelen J, Schoonbrood-Lenssen A, Willemse A, Beemer F, et al. (2001). Wolf–Hirschhorn (4p-) syndrome in adults. Genet Couns 12:35–48. Ogle R, O’Sillence DO, Merrick A, Ell J, Lo B, Robson L (1996). The Wolf–Hirschorn syndrome in adulthood: evaluation of a 24 year old man with a rec(4) chromosome. Am J Med Genet 65:124–127. Shannon NL, Maltby EL, Rigby AS, Quarrell OW (2001). An epidemiological study of Wolf–Hirschhorn syndrome: life expectancy and cause of mortality. J Med Genet 38:674–679. Smith SA, Walker AD, Monk AJ, Young ID (1995). Long term survival in the Wolf–Hirschorn (4p-) syndrome. J Ment Defic Res 39:83–86. Worthington JC, Rigby AS, Quarrell OW (2008). Seizure frequency in adults with Wolf–Hirschhorn syndrome. Am J Med Genet A 146A:2528–2531.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
