- Email: [email protected]
Early detection of chromosome 9q22.32q31.1 microdeletion and the nevoid basal cell carcinoma syndrome
European Journal of Medical Genetics 52 (2009) 145–147
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Chromosomal imbalance letter
Early detection of chromosome 9q22.32q31.1 microdeletion and the nevoid basal cell carcinoma syndrome Thomy J.L. de Ravel a, *, Liliane Ameye b, Katleen Ballon c, Martine Borghgraef a, Joris R. Vermeesch a, Koen Devriendt a a b c
Centre for Human Genetics, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium Algemeen Ziekenhuis Diest, Diest, Belgium Department of Paediatrics, University Hospitals Leuven, K.U. Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 December 2008 Accepted 10 February 2009 Available online 21 February 2009
We report on a patient with a microdeletion of chromosome region 9q22.32q31.1 including the PTCH1 gene (human homologue of the Drosophila patched 1 gene), review the findings in the reported patients with similar array CGH findings, and highlight the non nevoid basal cell carcinoma/non-Gorlin syndrome findings at an earlier age. These are macrocephaly, neonatal hypotonia, severe psychomotor retardation with markedly delayed motor milestones and speech development, epicanthic folds, a thin upper lip, a short and wide/webbed neck, pectus excavatum and (kypho)scoliosis. These features should alert the physician to an early diagnosis of the microdeletion and allow the initiation of essential clinical management hereof. Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords: Chromosome 9 Deletion 9q22.3 Array CGH Mental retardation PTCH1 Nevoid basal cell carcinoma
1. Method of detection
1.4. Cause of phenotype
1.1. Array CGH
Both parents were investigated by means of FISH using the RP11-23B15 probe, and found to be normal. The deletion is thus de novo.
The DNA of the patient was investigated using array comparative genomic hybridization (CGH) at a 1 Mb resolution with BAC and PAC clones [3]. 1.2. Chromosomal anomaly The array CGH indicated a deletion between 6.54 Mb and 8.12 Mb in size, the flanking clones being RP11-30L4 and RP11-75J9 (Fig. 2). The karyotype is 46,XY arr cgh 9q22.32q31.1(RP11-333I7– >RP11-80H12)x1. 1.3. Method of confirmation FISH using probe RP11-23B15 from within the deleted region confirmed the anomaly (Fig. 3).
* Corresponding author. Tel.: þ32 16 345903; fax: þ32 16 346051. E-mail address: [email protected] (T.J.L. de Ravel). 1769-7212/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2009.02.002
2. Clinical description This male patient of Turkish origin is the first child to non-consanguineous parents, both being 23 years at his birth. After an uneventful pregnancy, he was born at term by cesarean section, carried out due to a prolapsed cord. His Apgar score was 10, 9 and 9 at 1, 5 and 10 min respectively. His birth weight was 3800 g (75th centile), his length 53 cm (75–97th centile) and head circumference 35 cm (25–50th centile). He had a wide, short neck with a low nuchal hairline, epicanthic folds, long eyelashes, wide nasal bridge, low-set and posterior rotated ears, mild micrognathia, a short palate with a submucous cleft, wide cranial sutures and an open posterior fontanel. Upon examination at 5 weeks of age, he was alert and had good muscle tone. His head circumference had markedly increased to 39 cm (75th centile). Regurgitation of food through the nose was present. He had had numerous upper and lower respiratory track infections.
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T.J.L. de Ravel et al. / European Journal of Medical Genetics 52 (2009) 145–147
At 15 months of age, further dysmorphic features were noted. Although his weight was on the 50th centile, his length (84 cm) and head circumference (48.7 cm) were above the 97th centile. His chest was long and wide with widely spaced nipples, and he had small teeth and deep plantar grooves. He had moderate developmental delay and functioned at an 8–9 month level on Bayley Scales of Infant Development (BSID). He was not yet able to crawl but could walk if supported. He had not yet developed speech. His milestones continued to lag behind in that he functioned at a 19 month level at 27 months of age (Bayley Scales BSID-NL). He displayed distinct overgrowth with a height 3 cm above the 97th centile, had developed a pectus excavatum and large hands and feet, whilst his head growth had slowed down to between the 75th and 97th centiles. 3. Discussion Whereas interstitial deletions of the chromosome region 9q22.3 previously detected on Giemsa banding were between 10 and 17 Mb in size (reviewed in [1]), array CGH technologies now also detect submicroscopic imbalances. With the increased resolution even imbalances within a single gene can be detected. Table 1 lists the clinical features of the 7 patients with interstitial deletions
involving the chromosome 9q22.3 and specifically the PTCH1 gene (human homologue of the Drosophila patched 1 gene causal for the nevoid basal cell carcinoma/Gorlin syndrome), investigated by array CGH. These deletions vary from 11 Mb to 165 kb. The selection criteria of the studies were different and thus revealed different phenotypes. Fujii et al. [1] and Nowakowska et al. [4] further investigated patients (families) with nevoid basal cell carcinoma (NBCC) syndrome and in whom no point mutations had been found in the PTCH1 gene. These patients thus displayed features compatible with the syndrome. Of note is that patient G19 [1] had a 165 kb deletion involving only the PTCH1 gene and thus his clinical picture is strictly limited to the NBCC syndrome. The two cases of Redon et al. [5] and the present case had no clinical signs of the NBCC syndrome when screened but displayed overlapping features with the 3 other patients (G5 and G10 of [1], and the case of [4]). These all had deletions of the PTCH1 gene and contiguous regions, both centromeric and telomeric. The breakpoints of the deletions are all different (Fig. 1) and, as no sequence homology was found at the breakpoints analysed [4,5], non-allelic homologous recombination does not play a role here. Non-homologous end joining of DNA breaks is probably the cause of the deletions in patients G5 and G10 [1] and the 2 patients reported by Redon et al. [5]. Alu-mediated recombination is probably implicated in patient
Table 1 The clinical findings of the 7 patients with deletions encompassing the PTCH1 gene found on array CGH. The most frequently found non-NBCC syndrome features are in bold.
Sex G.A. B.W. B.L. B.H.C. Age at report Hypotonia Feeding Neonatal Skull Face
G19 [1]
G5 [1]
G10 [1]
[4]
Case 1 [5]
Case 2 [5]
Present case
Male NR NR NR >P97 at 10 yr 10 yr
Male NR NR NR >P97 at 12 yr 12 yr
Male NR NR NR >P97 8 yr
Female 41 3850 g(P75) 56 cm(>P95) 35 cm(P50) 12 yr
Male 40 4540 g(>P97) 55 cm(>P97) 39 cm(>P97) 5 yr
Female 40 5070 g(>P97) 53 cm(>P97) 41 cm(>P97) 8 yr
Male 40 3800 g(P75) 53 cm(P75) 35 cm(P25) 2 yr 3 m
Not present Problems
Neonatal NR
Neonatal NR
NR NR
Neonatal NR
Neonatal Neonatal
Not present Neonatal
Trigonocephaly
Trigonocephaly
Wide sutures
Coarse
Coarse
Coarse
Present
NR
High forehead, pointed chin Present
Present
Present
Present
Hypertelorism
Hypertelorism Strabismus, downslanting Strabismus palpebral fissures
Normal
Normal
High palate
NR
Strabismus, downslanting palpebral fissures Small mouth
Cysts 10 yr
Cysts 12 yr
Cysts NR
Normal excavatum
Webbed Not present
NR NR
Epicanthic None folds Eyes Hypertelorism
Mouth/ palate Lip Teeth/Jaw Neck Pectus Present Hernia Skin
None
High palate
Small mouth
Thin upper Delayed dentition, Cysts 12 yr Short NR
Thin upper Cysts NR
Inguinal Basal cell Carcinoma
2 cafe´ au lait, 1 hypopigmention Kyphoscoliosis, abnormal vertebrae, hypoplastic clavicles
Skeletal
Normal
Scoliosis
Scoliosis
Hands
Syndactyly
Palmar/plantar pits
Brain scan
Calcification falx/ tentorium cerebelli None None
Hydrocephalus, calcification falx/ tentorium cerebelli Severe Present Hydronephrosis
Palmar/plantar pits, polydactyly Hydrocephalus Cortical, subcortical atrophy
M.R. Epilepsy Other
Severe Present
Severe None Laryngeal stenosis, pulmonary valve stenosis
Short Present Umbilical 1 cafe´ au lait spot
Submucous cleft
Thin upper Thin upper Delayed dentition 8 yr, Mild micrognathia, small cysts NR teeth, no cysts at 4 jr Short Short wide Present Present Umbilical
None
Kyphosis 8 yr
Normal
Normal
Normal
Large ventricles, thin corpus callosum
Severe None Ears low-set with pits, lobule uplift
Severe Present at 3 yr Ears thick, low-set, lobule uplift, thyroglossal cyst
Dilated occipital horn of left lateral ventricle at 3 months of age Severe None Ears low-set, wide chest, spaced nipples
NR ¼ not reported/not known; G.A. ¼ gestational age in weeks at birth; B.W. ¼ birth weight; B.L. ¼ birth length; B.H.O. ¼ head circumference at birth; yr ¼ years; P ¼ centile; M.R. ¼ mental retardation.
T.J.L. de Ravel et al. / European Journal of Medical Genetics 52 (2009) 145–147
147
Chr. Bands PTCH1 gene [1] G5
(11.0 Mb)
[1] G10
(5.3 Mb)
[1] G19
(165 kb)
[5] Case 1 (6.5 Mb) [5] Case 2 (6.0 Mb) [4] Case
(7.7 Mb)
Present
(8.4 Mb)
Fig. 1. Figure representing the position of the PTCH1 gene and the microdeletion in the patients discussed (adapted to the [6]). The fine line protruding from the solid rectangles indicates the region between the minimal and maximal size of the deletion in the cases where the precise breakpoint in not known.
G19 [1]. The genes in the smallest common region of overlap of the microdeletions in these patients do not explain their mental retardation. The clinical symptoms of the NBCC syndrome are mostly age-dependent and post-pubertal. The major diagnostic criteria of the NBCC syndrome are basal cell carcinoma’s found in 15–100%, jaw cysts in 62–92%, palmar and/or plantar pits in 35–87%, and calcification of the falx cerebri in 21–92% of adults [reviewed in [2]]. The clinical suspicion of pre-pubertal patients with a contiguous gene deletion involving the PTCH1 gene will thus have to be based on the most frequent non-NBCC syndrome features (in bold in Table 1). These are macrocephaly, neonatal hypotonia, severe psychomotor retardation with markedly delayed motor milestones and speech development, epicanthic folds, a thin upper lip, a short and wide/webbed neck, pectus excavatum and (kypho)scoliosis. These features are present in at least 4 of the 6 patients. The pre-symptomatic follow-up of patients with contiguous gene deletions involving the PTCH1 gene includes all the surveillance recommended in patients with mutations within the gene [2]. - As the risk of medulloblastoma development is greatly increased during the first 7 years of life, 6-monthly clinical/ neurological evaluation is recommended during the first 3 years and once yearly between 3 and 7 years. Due to the nonNBCC syndrome features such as severe psychomotor retardation and epilepsy, these children are in practice assessed more frequently. CT scans are to be avoided due to the radiation harm. - Jaw cysts may start to develop from the age of 7 years and are usually multiple and thus, is once yearly monitoring by panorthogram recommended. A jaw cyst develops in 13% of cases by age 10 years, and 51% by age 21 years. Intervention will be carried out following on the clinical findings. - Skin lesions (NBCC) have on rare occasions been reported in children of 3 and 4 years of age. Regular assessment at least once a year is recommended starting from puberty as NBCC is then more likely to develop and be more aggressive. Although
not limited to sun-exposed areas, these areas are more affected, especially if sun exposure has not been avoided. In the patients with the contiguous gene deletion, a raised awareness and the regular monitoring for complications of hypotonia such as scoliosis is essential. Recognition of seizure onset and immediate and appropriate therapy are needed. In conclusion, we report on a patient with a microdeletion of chromosome region 9q22.32q31.1, review the findings in the reported patients with similar array CGH findings, and highlight the non-NBCC syndrome findings at an earlier age and the essential clinical management hereof. Appendix. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ejmg.2009.02.002. References [1] K. Fujii, S. Ishikawa, H. Uchikawa, D. Komura, M.H. Shapero, F. Shen, J. Hung, H. Arai, Y. Tanaka, K. Sasaki, Y. Kohno, M. Yamada, K.W. Jones, H. Aburatani, T. Miyashita, High density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome, Hum. Genet. 122 (2007) 459–466. [2] L. Lo Muzio, Nevoid basal cell carcinoma syndrome (Gorlin syndrome), Orphanet J. Rare Dis. 3 (2008) 32. [3] B. Menten, N. Maas, B. Thienpont, K. Buysse, J. Vandesompele, C. Melotte, T. de Ravel, S. Van Vooren, I. Balikova, L. Backx, S. Janssens, A. De Paepe, B. De Moor, Y. Moreau, P. Marynen, J.P. Fryns, G. Mortier, K. Devriendt, F. Speleman, J.R. Vermeesch, Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports, J. Med. Genet. 43 (2006) 625–633. [4] B. Nowakowska, A. Kutkowska-Kazmierczak, P. Stankiewicz, E. Bocian, E. Obersztyn, Z. Ou, S.W. Cheung, W. Cai, A girl with deletion 9q22.1-q22.32 including the PTCH1 and ROR2 genes identified by genome-wide array-CGH, Am. J. Med. Genet. 143A (2007) 1885–1889. [5] R. Redon, G. Baujat, D. Sanlaville, M. Le Merrer, M. Vekemans, A. Munnich, N.P. Carter, V. Cormier-Daire, L. Colleaux, Interstitial 9q22.3 microdeletion: clinical and molecular characterisation of a newly recognised overgrowth syndrome, Eur. J. Hum. Genet. 14 (2006) 759–767. [6] Ensembl release 52.http://www.ensembl.org (December 2008).
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Chromosomal imbalance letter
Early detection of chromosome 9q22.32q31.1 microdeletion and the nevoid basal cell carcinoma syndrome Thomy J.L. de Ravel a, *, Liliane Ameye b, Katleen Ballon c, Martine Borghgraef a, Joris R. Vermeesch a, Koen Devriendt a a b c
Centre for Human Genetics, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium Algemeen Ziekenhuis Diest, Diest, Belgium Department of Paediatrics, University Hospitals Leuven, K.U. Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 December 2008 Accepted 10 February 2009 Available online 21 February 2009
We report on a patient with a microdeletion of chromosome region 9q22.32q31.1 including the PTCH1 gene (human homologue of the Drosophila patched 1 gene), review the findings in the reported patients with similar array CGH findings, and highlight the non nevoid basal cell carcinoma/non-Gorlin syndrome findings at an earlier age. These are macrocephaly, neonatal hypotonia, severe psychomotor retardation with markedly delayed motor milestones and speech development, epicanthic folds, a thin upper lip, a short and wide/webbed neck, pectus excavatum and (kypho)scoliosis. These features should alert the physician to an early diagnosis of the microdeletion and allow the initiation of essential clinical management hereof. Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords: Chromosome 9 Deletion 9q22.3 Array CGH Mental retardation PTCH1 Nevoid basal cell carcinoma
1. Method of detection
1.4. Cause of phenotype
1.1. Array CGH
Both parents were investigated by means of FISH using the RP11-23B15 probe, and found to be normal. The deletion is thus de novo.
The DNA of the patient was investigated using array comparative genomic hybridization (CGH) at a 1 Mb resolution with BAC and PAC clones [3]. 1.2. Chromosomal anomaly The array CGH indicated a deletion between 6.54 Mb and 8.12 Mb in size, the flanking clones being RP11-30L4 and RP11-75J9 (Fig. 2). The karyotype is 46,XY arr cgh 9q22.32q31.1(RP11-333I7– >RP11-80H12)x1. 1.3. Method of confirmation FISH using probe RP11-23B15 from within the deleted region confirmed the anomaly (Fig. 3).
* Corresponding author. Tel.: þ32 16 345903; fax: þ32 16 346051. E-mail address: [email protected] (T.J.L. de Ravel). 1769-7212/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2009.02.002
2. Clinical description This male patient of Turkish origin is the first child to non-consanguineous parents, both being 23 years at his birth. After an uneventful pregnancy, he was born at term by cesarean section, carried out due to a prolapsed cord. His Apgar score was 10, 9 and 9 at 1, 5 and 10 min respectively. His birth weight was 3800 g (75th centile), his length 53 cm (75–97th centile) and head circumference 35 cm (25–50th centile). He had a wide, short neck with a low nuchal hairline, epicanthic folds, long eyelashes, wide nasal bridge, low-set and posterior rotated ears, mild micrognathia, a short palate with a submucous cleft, wide cranial sutures and an open posterior fontanel. Upon examination at 5 weeks of age, he was alert and had good muscle tone. His head circumference had markedly increased to 39 cm (75th centile). Regurgitation of food through the nose was present. He had had numerous upper and lower respiratory track infections.
146
T.J.L. de Ravel et al. / European Journal of Medical Genetics 52 (2009) 145–147
At 15 months of age, further dysmorphic features were noted. Although his weight was on the 50th centile, his length (84 cm) and head circumference (48.7 cm) were above the 97th centile. His chest was long and wide with widely spaced nipples, and he had small teeth and deep plantar grooves. He had moderate developmental delay and functioned at an 8–9 month level on Bayley Scales of Infant Development (BSID). He was not yet able to crawl but could walk if supported. He had not yet developed speech. His milestones continued to lag behind in that he functioned at a 19 month level at 27 months of age (Bayley Scales BSID-NL). He displayed distinct overgrowth with a height 3 cm above the 97th centile, had developed a pectus excavatum and large hands and feet, whilst his head growth had slowed down to between the 75th and 97th centiles. 3. Discussion Whereas interstitial deletions of the chromosome region 9q22.3 previously detected on Giemsa banding were between 10 and 17 Mb in size (reviewed in [1]), array CGH technologies now also detect submicroscopic imbalances. With the increased resolution even imbalances within a single gene can be detected. Table 1 lists the clinical features of the 7 patients with interstitial deletions
involving the chromosome 9q22.3 and specifically the PTCH1 gene (human homologue of the Drosophila patched 1 gene causal for the nevoid basal cell carcinoma/Gorlin syndrome), investigated by array CGH. These deletions vary from 11 Mb to 165 kb. The selection criteria of the studies were different and thus revealed different phenotypes. Fujii et al. [1] and Nowakowska et al. [4] further investigated patients (families) with nevoid basal cell carcinoma (NBCC) syndrome and in whom no point mutations had been found in the PTCH1 gene. These patients thus displayed features compatible with the syndrome. Of note is that patient G19 [1] had a 165 kb deletion involving only the PTCH1 gene and thus his clinical picture is strictly limited to the NBCC syndrome. The two cases of Redon et al. [5] and the present case had no clinical signs of the NBCC syndrome when screened but displayed overlapping features with the 3 other patients (G5 and G10 of [1], and the case of [4]). These all had deletions of the PTCH1 gene and contiguous regions, both centromeric and telomeric. The breakpoints of the deletions are all different (Fig. 1) and, as no sequence homology was found at the breakpoints analysed [4,5], non-allelic homologous recombination does not play a role here. Non-homologous end joining of DNA breaks is probably the cause of the deletions in patients G5 and G10 [1] and the 2 patients reported by Redon et al. [5]. Alu-mediated recombination is probably implicated in patient
Table 1 The clinical findings of the 7 patients with deletions encompassing the PTCH1 gene found on array CGH. The most frequently found non-NBCC syndrome features are in bold.
Sex G.A. B.W. B.L. B.H.C. Age at report Hypotonia Feeding Neonatal Skull Face
G19 [1]
G5 [1]
G10 [1]
[4]
Case 1 [5]
Case 2 [5]
Present case
Male NR NR NR >P97 at 10 yr 10 yr
Male NR NR NR >P97 at 12 yr 12 yr
Male NR NR NR >P97 8 yr
Female 41 3850 g(P75) 56 cm(>P95) 35 cm(P50) 12 yr
Male 40 4540 g(>P97) 55 cm(>P97) 39 cm(>P97) 5 yr
Female 40 5070 g(>P97) 53 cm(>P97) 41 cm(>P97) 8 yr
Male 40 3800 g(P75) 53 cm(P75) 35 cm(P25) 2 yr 3 m
Not present Problems
Neonatal NR
Neonatal NR
NR NR
Neonatal NR
Neonatal Neonatal
Not present Neonatal
Trigonocephaly
Trigonocephaly
Wide sutures
Coarse
Coarse
Coarse
Present
NR
High forehead, pointed chin Present
Present
Present
Present
Hypertelorism
Hypertelorism Strabismus, downslanting Strabismus palpebral fissures
Normal
Normal
High palate
NR
Strabismus, downslanting palpebral fissures Small mouth
Cysts 10 yr
Cysts 12 yr
Cysts NR
Normal excavatum
Webbed Not present
NR NR
Epicanthic None folds Eyes Hypertelorism
Mouth/ palate Lip Teeth/Jaw Neck Pectus Present Hernia Skin
None
High palate
Small mouth
Thin upper Delayed dentition, Cysts 12 yr Short NR
Thin upper Cysts NR
Inguinal Basal cell Carcinoma
2 cafe´ au lait, 1 hypopigmention Kyphoscoliosis, abnormal vertebrae, hypoplastic clavicles
Skeletal
Normal
Scoliosis
Scoliosis
Hands
Syndactyly
Palmar/plantar pits
Brain scan
Calcification falx/ tentorium cerebelli None None
Hydrocephalus, calcification falx/ tentorium cerebelli Severe Present Hydronephrosis
Palmar/plantar pits, polydactyly Hydrocephalus Cortical, subcortical atrophy
M.R. Epilepsy Other
Severe Present
Severe None Laryngeal stenosis, pulmonary valve stenosis
Short Present Umbilical 1 cafe´ au lait spot
Submucous cleft
Thin upper Thin upper Delayed dentition 8 yr, Mild micrognathia, small cysts NR teeth, no cysts at 4 jr Short Short wide Present Present Umbilical
None
Kyphosis 8 yr
Normal
Normal
Normal
Large ventricles, thin corpus callosum
Severe None Ears low-set with pits, lobule uplift
Severe Present at 3 yr Ears thick, low-set, lobule uplift, thyroglossal cyst
Dilated occipital horn of left lateral ventricle at 3 months of age Severe None Ears low-set, wide chest, spaced nipples
NR ¼ not reported/not known; G.A. ¼ gestational age in weeks at birth; B.W. ¼ birth weight; B.L. ¼ birth length; B.H.O. ¼ head circumference at birth; yr ¼ years; P ¼ centile; M.R. ¼ mental retardation.
T.J.L. de Ravel et al. / European Journal of Medical Genetics 52 (2009) 145–147
147
Chr. Bands PTCH1 gene [1] G5
(11.0 Mb)
[1] G10
(5.3 Mb)
[1] G19
(165 kb)
[5] Case 1 (6.5 Mb) [5] Case 2 (6.0 Mb) [4] Case
(7.7 Mb)
Present
(8.4 Mb)
Fig. 1. Figure representing the position of the PTCH1 gene and the microdeletion in the patients discussed (adapted to the [6]). The fine line protruding from the solid rectangles indicates the region between the minimal and maximal size of the deletion in the cases where the precise breakpoint in not known.
G19 [1]. The genes in the smallest common region of overlap of the microdeletions in these patients do not explain their mental retardation. The clinical symptoms of the NBCC syndrome are mostly age-dependent and post-pubertal. The major diagnostic criteria of the NBCC syndrome are basal cell carcinoma’s found in 15–100%, jaw cysts in 62–92%, palmar and/or plantar pits in 35–87%, and calcification of the falx cerebri in 21–92% of adults [reviewed in [2]]. The clinical suspicion of pre-pubertal patients with a contiguous gene deletion involving the PTCH1 gene will thus have to be based on the most frequent non-NBCC syndrome features (in bold in Table 1). These are macrocephaly, neonatal hypotonia, severe psychomotor retardation with markedly delayed motor milestones and speech development, epicanthic folds, a thin upper lip, a short and wide/webbed neck, pectus excavatum and (kypho)scoliosis. These features are present in at least 4 of the 6 patients. The pre-symptomatic follow-up of patients with contiguous gene deletions involving the PTCH1 gene includes all the surveillance recommended in patients with mutations within the gene [2]. - As the risk of medulloblastoma development is greatly increased during the first 7 years of life, 6-monthly clinical/ neurological evaluation is recommended during the first 3 years and once yearly between 3 and 7 years. Due to the nonNBCC syndrome features such as severe psychomotor retardation and epilepsy, these children are in practice assessed more frequently. CT scans are to be avoided due to the radiation harm. - Jaw cysts may start to develop from the age of 7 years and are usually multiple and thus, is once yearly monitoring by panorthogram recommended. A jaw cyst develops in 13% of cases by age 10 years, and 51% by age 21 years. Intervention will be carried out following on the clinical findings. - Skin lesions (NBCC) have on rare occasions been reported in children of 3 and 4 years of age. Regular assessment at least once a year is recommended starting from puberty as NBCC is then more likely to develop and be more aggressive. Although
not limited to sun-exposed areas, these areas are more affected, especially if sun exposure has not been avoided. In the patients with the contiguous gene deletion, a raised awareness and the regular monitoring for complications of hypotonia such as scoliosis is essential. Recognition of seizure onset and immediate and appropriate therapy are needed. In conclusion, we report on a patient with a microdeletion of chromosome region 9q22.32q31.1, review the findings in the reported patients with similar array CGH findings, and highlight the non-NBCC syndrome findings at an earlier age and the essential clinical management hereof. Appendix. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ejmg.2009.02.002. References [1] K. Fujii, S. Ishikawa, H. Uchikawa, D. Komura, M.H. Shapero, F. Shen, J. Hung, H. Arai, Y. Tanaka, K. Sasaki, Y. Kohno, M. Yamada, K.W. Jones, H. Aburatani, T. Miyashita, High density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome, Hum. Genet. 122 (2007) 459–466. [2] L. Lo Muzio, Nevoid basal cell carcinoma syndrome (Gorlin syndrome), Orphanet J. Rare Dis. 3 (2008) 32. [3] B. Menten, N. Maas, B. Thienpont, K. Buysse, J. Vandesompele, C. Melotte, T. de Ravel, S. Van Vooren, I. Balikova, L. Backx, S. Janssens, A. De Paepe, B. De Moor, Y. Moreau, P. Marynen, J.P. Fryns, G. Mortier, K. Devriendt, F. Speleman, J.R. Vermeesch, Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports, J. Med. Genet. 43 (2006) 625–633. [4] B. Nowakowska, A. Kutkowska-Kazmierczak, P. Stankiewicz, E. Bocian, E. Obersztyn, Z. Ou, S.W. Cheung, W. Cai, A girl with deletion 9q22.1-q22.32 including the PTCH1 and ROR2 genes identified by genome-wide array-CGH, Am. J. Med. Genet. 143A (2007) 1885–1889. [5] R. Redon, G. Baujat, D. Sanlaville, M. Le Merrer, M. Vekemans, A. Munnich, N.P. Carter, V. Cormier-Daire, L. Colleaux, Interstitial 9q22.3 microdeletion: clinical and molecular characterisation of a newly recognised overgrowth syndrome, Eur. J. Hum. Genet. 14 (2006) 759–767. [6] Ensembl release 52.http://www.ensembl.org (December 2008).