- Email: [email protected]
A further patient with van Maldergem syndrome
European Journal of Medical Genetics 55 (2012) 423e428
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short clinical report
A further patient with van Maldergem syndrome T.M. Neuhann a, b, *, D. Müller a, K. Hackmann a, S. Holzinger c, E. Schrock a, N. Di Donato a a
Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Medizinisch Genetisches Zentrum, Bayerstr. 3-5, Munich 80335, Germany c Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 December 2011 Accepted 27 February 2012 Available online 13 March 2012
We report on a male patient with the proposed diagnosis of the rare but very distinct entity of van Maldergem syndrome. His parents are first cousins. At the age of 4 years the boy presented with severe developmental delay, talipes equinovarus, finger camptodactyly with interphalangeal pterygium, joint laxity, bilateral microtia, and a dysmorphic facies. He showed bilateral epicanthus, telecanthus, short palpebral fissures, broad flat nasal bridge, and dental malocclusion. The combination of the specific facial features with camptodactyly, interphalangeal pterygium, joint laxity and developmental delay led to the diagnosis of van Maldergem syndrome. The medical history was further on significant for pharyngeal instability requiring the placement of a tracheostomy tube, an inguinal hernia, hip subluxation, small kidneys and genital abnormalities (micropenis, bifid scrotum, cryptorchidism). Due to severe feeding difficulties permanent tube feeding was required. Metabolic tests (newborn metabolic screening, 7-dehydrocholesterol, amino acids, organic acids in urine) and chromosomal analysis (450e500 bands; 46,XY) were normal. Molecular karyotyping revealed two parental CNVs (paternal deletion of 9q33.1; maternal duplication of 11p15.1), which are unlikely to contribute to the patient’s phenotype. Taken together, the report on a further patient with van Maldergem syndrome expands the clinical spectrum of the condition by adding genital malformations, hernia, pharyngeal instability, and subluxation of the hip. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Syndactyly Camptodactyly Clubfoot deformity Microtia Genital malformation Developmental delay van Maldergem syndrome
1. Introduction A new entity was described in a female patient by van Maldergem and cowokers [1] in 1992. The girl showed a very specific facial dysmorphism that includes telecanthus, epicanthus, short palpebral fissures, dental anomalies, and dysplastic ears; also, she had camptodactyly of the fingers, interdigital webbing, joint laxity and talipes. The neurological phenotype comprised neonatal hypotonia, intellectual disability, and hyperkinetic behavior at older age. A further patient was reported by Zampino et al. in 1994 [2]. This patient had similar facial features (telecanthus, epicanthal folds, low set and small ears, dental malocclusion) and hand malformations (syndactyly, camptodactyly); the girl also showed joint laxity and pes talus valgus, mastication difficulties, hypotonia, agenesis of corpus callosum, and severe intellectual disability.
* Corresponding author. Medizinisch Genetisches Zentrum, Bayerstr. 3-5, Munich 80335, Germany. Tel.: þ49 89 30908860; fax: þ49 89 309088666. E-mail address: [email protected] (T.M. Neuhann). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.02.012
Here we report on a male patient born to consanguineous parents, with the distinct combination of the major and minor anomalies described for van Maldergem syndrome. 2. Clinical report The patient was born as the first common child of healthy consanguineous caucasian parents (first cousins). He has both maternal and paternal healthy half-siblings. A maternal uncle suffered from seizures. The mother and four of the maternal halfsiblings attended a special school. The first pregnancy of the parents ended with a spontaneous abortion in the 8th gestational week (GW). The pregnancy was complicated by gestational diabetes of the mother, which was apparent from the 20th GW. The boy was born after 37 GW. Birth measurement were within the normal range: occipital-frontal head circumference (OFC) 34 cm (0.3 SD), length 50 cm (0.1 SD), weight 3120 g (0.1 SD). In the pathological examination of the placenta a single umbilical artery was noticed. Immediately after birth, he had hypotonia and pronounced swallowing difficulties and required a nasogastral tube. It was later
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replaced by a PEG (percutaneous endoscopic gastrostomy) tube. Furthermore, bilateral microtia, contractures and cutaneous syndactylies of fingers IIeV, ulnar deviation of both hands, cutaneous syndactyly of toes, bilateral club feet, and genital malformations (micropenis, bifid scrotum) were apparent. Abdominal ultrasound examination revealed bilateral hypoplastic kidneys. Extremely narrow auditory channels complicated examination of the ears by an ENT specialist; the tympanic membrane was not visualized. An MRI scan of the brain was performed in the first month of life; apart from a hypoplastic corpus callosum (Fig. 1) it was considered as normal, including inner ear structures. The ultrasound examination of the medulla showed a cystic structure at the conus medullaris suggesting the presence of a fifth ventricle. Cardiac ultrasound was normal. An ophthalmologic evaluation showed no intraocular malformations. The patient suffered from pharyngeal dysfunction with consecutive recurrent pneumonias; thus, tracheostomy was performed at the age of 17 months. It could successfully be removed at the age of 4 years. Within the first year of life he underwent surgery for bilateral inguinal hernias and orchidopexia was performed. Due to the subluxation of the hips derotational varising femoral osteotomy was performed at the age of 4 years. Psychomotor development of the boy was markedly delayed. He sat without support at the age of 26 months. At the age of 4 years, he was not able to walk and also there was no speech development. At the clinical evaluation at the age of 4 years and 2 months the length was 96 cm (2.1 SDS), OFC 48 cm (2.5 SDS), and weight was 12.7 kg (BMI 13.78). The boy had distinct facial dysmorphic features: prominent forehead with a high frontal hairline, telecanthus, bilateral epicanthic folds, narrow palpebral fissures, full cheeks, small nose with depressed nasal bridge, small and hypotonic mouth, irregular alignment of teeth, and bilateral microtia (Fig. 2). Both elbow and knee joints were hypermobile. Fingers IIeV had cutaneous syndactylies and webbing between the proximal and distal phalanges, “phalangeal pterygium” (Fig. 3). Besides bilateral clubfoot deformity the examination of the feet showed bilateral cutaneous syndactyly of toes II and III (Fig. 4). The thorax had an asymmetric shape and the mammillae were hypoplastic. Besides the genital malformation mentioned above (micropenis, bifid scrotum) an antepositioned anus and a sacral dimple were noted. He had muscular hypotonia.
3. Investigations All investigations including newborn metabolic screening and comprehensive genetic studies could not clarify the underlying cause of the syndromic condition. Analyses performed include routine karyotyping, biochemical investigations (7-dehydrocholesterol regarding SmitheLemlieOpitz syndrome, amino acids, organic acids in urine), and high resolution molecular karyotyping. Oligo microarray analysis using Agilent’s SurePrint G3 Human CGH Microarray Kit 2 400 K (Design ID 021850, Agilent, Santa Clara, CA, USA) revealed two copy number variations (CNV), one inherited from the unaffected father and the other from the unaffected mother: arr9q33.1 (119,318,986x2, 119,332,835119,361,232x1, 119,366,231x2)pat, arr11p15.1 (20,808,651x2, 20,804,606e20,969,024x3, 20,973,131x2)mat (GRCh37/hg19). The deleted region in 9q33.1 contains only intronic sequences of the ASTN2 gene. DECIPHER patient 259298 with the overlapping 9q33.1 deletion of 300 kb (phenotype not known) also inherited it from the unaffected parent. The duplication within subband 11p15.1 includes several exons of the NELL1 gene, which has so far not been associated with known intellectual disability syndromes. A biallelic mutation of NELL1 in mice leads to a complex phenotype including impaired development of the intervertebral discs, vertebrae, and calvarian bones, and perinatal lethality [3]. However, the duplication was also present in the mother who did not resemble a similar phenotype as her son. Moreover, a deletion of several exons of the NELL1 gene was observed within our own patient group, which was also inherited from the healthy parent. In summary, both aberrations are considered to be benign and unlikely to be of relevance for the phenotype [4]. 4. Discussion The main features of van Maldergem syndrome can be summarized as moderate to severe intellectual disability, hypotonia, distinctive combination of minor facial anomalies, finger camptodactyly, and joint hyperlaxity. Due to the facial dysmorphism and the additional malformations e especially regarding the hands with camptodactyly, syndactyly, and interphalangeal pterygium in the reported patient the diagnosis of van Maldergem syndrome was established. The similarity of his facial features to the two patients from the literature is very striking; also the skeletal (syndactyly and
Fig. 1. Cranial MRI scan taken of the patient at the age of 1 month, transverse (a) and coronal (b) T1-weighted sequences, showing hypoplasia of the corpus callosum.
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Fig. 2. Patient at the age of 2 years and 10 month (a) and at the age of 4 years and 2 months. (b) Note hypotonic expressionless face, high frontal hairline, bilateral epicanthus, telecanthus, short palpebral fissures, depressed nasal bridge, short nose, open mouth appearance, dental malocclusion, and bilateral microtia.
camptodactyly, joint laxity, talipes) and neurological phenotype (hypotonia, intellectual disability) is very similar (Table 1). The patient presented here does show some additional features: he is the first male patient with this condition and had malformations of the external genitalia (micropenis, bifid scrotum, cryptorchidism); also, the boy had pharyngeal instability, bilateral inguinal hernias, and hip dysplasia. These features might also belong to the extended phenotype of van Maldergem syndrome. Since the parents of the patient are consanguineous, autosomal recessive inheritance is likely; however, autosomal dominant inheritance due to a novel mutation cannot be excluded. With a boy and two girls affected, X chromosomal inheritance seems less likely.
Since the phenotype of the patient is very distinct, only few differential diagnoses had enough overlapping features to be considered. These were evaluated by a search with different combinations of the minor and major anomalies present (“telecanthus”, “microtia “, ‘‘syndactyly”, “camptodactyly”, “club foot deformity”, “joint laxity”, “intellectual disability’’) which led to an extensive list of syndromic conditions. However, most of the possible differential diagnoses could be excluded based on the absence of specific features (e.g. Aarskog syndrome, ATRX syndrome, acrofacial dysostosis, SaethreeChotzen syndrome, SmitheLemlieOpitz syndrome).
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Fig. 3. Hands of the patient. Note cutaneous syndactyly and interphalangeal webbing.
4.1. Blepharo-naso-facial syndrome This condition was considered as a differential diagnosis by van Maldergem et al. [1]. Although some of the features overlap (telecanthus, syndactyly, joint laxity, intellectual
disability), these patients do not have the ear malformations and camptodactyly as seen in the patient described here. Also, some of the major features (lacrimal duct obstruction, extrapyramidal disorders) described in this condition [5e7] are absent in the reported patient which makes the diagnosis
Fig. 4. Feet of the patient at the age of 4 years and 2 months. The feet had been redressed due to bilateral clubfoot deformity since the first year of life. Additionally, there is cutaneous syndactyly of toes II and III.
T.M. Neuhann et al. / European Journal of Medical Genetics 55 (2012) 423e428
427
Table 1 Clinical features of the 3 patients with van Maldergem syndrome. Van Maldergem et al.
Zampino et al.
Present patient
Gender Age Height OFC Frontal hairline Telecanthusa Epicanthus Downslanting palpebral fissures Ptosis Dental malocclusion W-shaped upper lip Everted lower lip Macrostomia Downturned mouth Microtia/dysplastic ears Camptodactyly Syndactyly Talipes Joint hyperlaxity Hypotonia IDb Hyperkinesia Ataxia CNS malformation
F 11 y 50th centile 3rd centile Low D D D þ D D þ þ D D D D D D D Moderate þ e e
M 4y2m <3rd centile (2.1 SD) <3rd centile (2,5 SD) High D D D e D D e e D D D D/Interdigital pterygium D D D Severe e e Hypoplastic corpus callosum
Genital abnormalitiesc Pharyngeal dysfunction with feeding difficulties Hypoplastic kidneys
e e e
F 5y6m 75th centile 10th centile Low D D D þ D D þ þ D D D D D D D Severe þ þ Hypoplastic corpus callosum, cerebellar and pons hypoplasia e e e
a b c
þ þ þ
Overlapping features are highlighted in bold. ID e intellectual disability. New features in the patient described in this report are highlighted in italics.
of blepharo-naso-facial syndrome in the reported patient unlikely. 4.2. Hennekam syndrome Hennekam et al. [8] described a syndrome with unusual face that does resemble the facial dysmorphism of our patient and of the patients with van Maldergem syndrome from the literature; besides microtia the ocular and dental malformations are similar, also intellectual disability is a feature of Hennekam syndrome. However, camptodactyly and syndactyly, although been described [9], are not a consistent feature. Moreover, patients with Hennekam syndrome show a significant lymphedema e a feature that has not been observed in our patient nor the two published van Maldergem syndrome patients. 4.3. WintereTsukahara syndrome This syndrome has so far only been described in a few patients [10e12]. Again, the facial features do share similarities with the patients with van Maldergem syndrom and the present case. Also genital malformations and camptodacytly have been described. However, in these patients pachygyria is a common feature, which was not observed in the patients with van Maldergem syndrome. 4.4. EastmaneBixler syndrome This facio-cardio-renal syndrome was first described in 1977 [13]. Besides the facial features (telecanthus, microtia, dental anomalies), finger syndactyly, and genital malformations, this syndrome is further characterized by cleft palate, renal malformations (especially horseshoe kidney), and cardiac anomalies (endocardial fibroelastosis, conduction defects) [13e15]. The latter malformations are not present in our patient.
In conclusion, the presented case report further delineates the very characteristic entity of van Maldergem syndrome. The presented patient adds additional features to the phenotype such as genital malformation, and the clinical course of the condition e pharyngeal instability and feeding difficulties. Since both male and female patients are known and the parents of our patient are consanguineous, autosomal recessive inheritance is proposed. Acknowledgments We thank the family for their boundless cooperation. Furthermore, we would like to thank Dr. L. van Maldergem for confirming the diagnosis and Dr. M. Notohamiprodjo for his support regarding the MRI pictures. This work was supported by the Bundesministerium für Bildung und Forschung (BMBF) network grant MR-NET 01GS08166. References [1] L. van Maldergem, C. Wetzburger, A. Verloes, C. Fourneau, Y. Gillerot, Mental retardation with blepharo-naso-facial abnormalities and hand malformations: a new syndrome? Clin. Genet. 41 (1992) 22e24. [2] G. Zampino, C. Colosimo, F. Balducci, P. Mariotti, F. Serra, G. Scarano, P. Mastroiacovo, Cerebro-facio-articular syndrome of van Maldergem: confirmation of a new MR/MCA syndrome, Clin. Genet. 45 (1994) 140e144. [3] J. Desai, M.E. Shannon, M.D. Johnson, D.W. Ruff, L.A. Hughes, M.K. Kerley, D.A. Carpenter, D.K. Johnson, E.M. Rinchik, C.T. Culiat, Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects, Hum. Mol. Genet. 15 (2006) 1329e1341. [4] D.A. Koolen, R. Pfundt, N. de Leeuw, J.Y. Hehir-Kwa, W.M. Nillesen, I. Neefs, I. Scheltinga, E. Sistermans, D. Smeets, H.G. Brunner, A.G. van Kessel, J.A. Veltman, B.B. de Vries, Genomic microarrays in mental retardation: a practical workflow for diagnostic applications, Hum. Mutat. 30 (2009) 283e292. [5] J.E. Allanson, A second family with blepharo-naso-facial syndrome, Clin. Dysmorphol. 11 (2002) 191e194. [6] H. Pashayan, S. Pruzansky, A. Putterman, A family with blepharo-naso-facial malformations, Am. J. Dis. Child. 125 (1973) 389e393.
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[7] A.M. Putterman, H. Pashayan, S. Pruzansky, Eye findings in the blepharo-nasofacial malformation syndrome, Am. J. Ophthalmol. 76 (1973) 825e831. [8] R.C. Hennekam, R.A. Geerdink, B.C. Hamel, F.A. Hennekam, P. Kraus, J.A. Rammeloo, A.A. Tillemans, Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation, Am. J. Med. Genet. 34 (1989) 593e600. [9] O. Gabrielli, C. Catassi, A. Carlucci, G.V. Coppa, P. Giorgi, Intestinal lymphangiectasia, lymphedema, mental retardation, and typical face: confirmation of the Hennekam syndrome, Am. J. Med. Genet. 40 (1991) 244e247. [10] R.M. Winter, B.N. Harding, J. Hyde, Unknown syndrome: pachygyria, joint contractures, and facial abnormalities, J. Med. Genet. 26 (1989) 788e789.
[11] M. Tsukahara, Y. Sugio, T. Kajii, M. Takahashi, M. Hirota, H. Kato, Pachygyria, joint contractures, and facial abnormalities: a new lethal syndrome, J. Med. Genet. 27 (1990) 532. [12] M.L. Levin, J.R. Lupski, R.J. Carpenter Jr., L.P. Gerson, F. Greenberg, An additional case of pachygyria, joint contractures and facial abnormalities, Clin. Dysmorphol. 2 (1993) 365e368. [13] J.R. Eastman, D. Bixler, Facio-cardio-renal syndrome: a newly delineated recessive disorder, Clin. Genet. 11 (1977) 424e430. [14] N.C. Nevin, A.E. Hill, D.J. Carson, Facio-cardio-renal (Eastman-Bixler) syndrome, Am. J. Med. Genet. 40 (1991) 31e33. [15] D. Martinet, Y. Vial, F. Thonney, J.S. Beckmann, K. Meagher-Villemure, S. Unger, Fetus with two identical reciprocal translocations: description of a rare complication of consanguinity, Am. J. Med. Genet. A 140 (2006) 769e774.
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short clinical report
A further patient with van Maldergem syndrome T.M. Neuhann a, b, *, D. Müller a, K. Hackmann a, S. Holzinger c, E. Schrock a, N. Di Donato a a
Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Medizinisch Genetisches Zentrum, Bayerstr. 3-5, Munich 80335, Germany c Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 December 2011 Accepted 27 February 2012 Available online 13 March 2012
We report on a male patient with the proposed diagnosis of the rare but very distinct entity of van Maldergem syndrome. His parents are first cousins. At the age of 4 years the boy presented with severe developmental delay, talipes equinovarus, finger camptodactyly with interphalangeal pterygium, joint laxity, bilateral microtia, and a dysmorphic facies. He showed bilateral epicanthus, telecanthus, short palpebral fissures, broad flat nasal bridge, and dental malocclusion. The combination of the specific facial features with camptodactyly, interphalangeal pterygium, joint laxity and developmental delay led to the diagnosis of van Maldergem syndrome. The medical history was further on significant for pharyngeal instability requiring the placement of a tracheostomy tube, an inguinal hernia, hip subluxation, small kidneys and genital abnormalities (micropenis, bifid scrotum, cryptorchidism). Due to severe feeding difficulties permanent tube feeding was required. Metabolic tests (newborn metabolic screening, 7-dehydrocholesterol, amino acids, organic acids in urine) and chromosomal analysis (450e500 bands; 46,XY) were normal. Molecular karyotyping revealed two parental CNVs (paternal deletion of 9q33.1; maternal duplication of 11p15.1), which are unlikely to contribute to the patient’s phenotype. Taken together, the report on a further patient with van Maldergem syndrome expands the clinical spectrum of the condition by adding genital malformations, hernia, pharyngeal instability, and subluxation of the hip. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Syndactyly Camptodactyly Clubfoot deformity Microtia Genital malformation Developmental delay van Maldergem syndrome
1. Introduction A new entity was described in a female patient by van Maldergem and cowokers [1] in 1992. The girl showed a very specific facial dysmorphism that includes telecanthus, epicanthus, short palpebral fissures, dental anomalies, and dysplastic ears; also, she had camptodactyly of the fingers, interdigital webbing, joint laxity and talipes. The neurological phenotype comprised neonatal hypotonia, intellectual disability, and hyperkinetic behavior at older age. A further patient was reported by Zampino et al. in 1994 [2]. This patient had similar facial features (telecanthus, epicanthal folds, low set and small ears, dental malocclusion) and hand malformations (syndactyly, camptodactyly); the girl also showed joint laxity and pes talus valgus, mastication difficulties, hypotonia, agenesis of corpus callosum, and severe intellectual disability.
* Corresponding author. Medizinisch Genetisches Zentrum, Bayerstr. 3-5, Munich 80335, Germany. Tel.: þ49 89 30908860; fax: þ49 89 309088666. E-mail address: [email protected] (T.M. Neuhann). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.02.012
Here we report on a male patient born to consanguineous parents, with the distinct combination of the major and minor anomalies described for van Maldergem syndrome. 2. Clinical report The patient was born as the first common child of healthy consanguineous caucasian parents (first cousins). He has both maternal and paternal healthy half-siblings. A maternal uncle suffered from seizures. The mother and four of the maternal halfsiblings attended a special school. The first pregnancy of the parents ended with a spontaneous abortion in the 8th gestational week (GW). The pregnancy was complicated by gestational diabetes of the mother, which was apparent from the 20th GW. The boy was born after 37 GW. Birth measurement were within the normal range: occipital-frontal head circumference (OFC) 34 cm (0.3 SD), length 50 cm (0.1 SD), weight 3120 g (0.1 SD). In the pathological examination of the placenta a single umbilical artery was noticed. Immediately after birth, he had hypotonia and pronounced swallowing difficulties and required a nasogastral tube. It was later
424
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replaced by a PEG (percutaneous endoscopic gastrostomy) tube. Furthermore, bilateral microtia, contractures and cutaneous syndactylies of fingers IIeV, ulnar deviation of both hands, cutaneous syndactyly of toes, bilateral club feet, and genital malformations (micropenis, bifid scrotum) were apparent. Abdominal ultrasound examination revealed bilateral hypoplastic kidneys. Extremely narrow auditory channels complicated examination of the ears by an ENT specialist; the tympanic membrane was not visualized. An MRI scan of the brain was performed in the first month of life; apart from a hypoplastic corpus callosum (Fig. 1) it was considered as normal, including inner ear structures. The ultrasound examination of the medulla showed a cystic structure at the conus medullaris suggesting the presence of a fifth ventricle. Cardiac ultrasound was normal. An ophthalmologic evaluation showed no intraocular malformations. The patient suffered from pharyngeal dysfunction with consecutive recurrent pneumonias; thus, tracheostomy was performed at the age of 17 months. It could successfully be removed at the age of 4 years. Within the first year of life he underwent surgery for bilateral inguinal hernias and orchidopexia was performed. Due to the subluxation of the hips derotational varising femoral osteotomy was performed at the age of 4 years. Psychomotor development of the boy was markedly delayed. He sat without support at the age of 26 months. At the age of 4 years, he was not able to walk and also there was no speech development. At the clinical evaluation at the age of 4 years and 2 months the length was 96 cm (2.1 SDS), OFC 48 cm (2.5 SDS), and weight was 12.7 kg (BMI 13.78). The boy had distinct facial dysmorphic features: prominent forehead with a high frontal hairline, telecanthus, bilateral epicanthic folds, narrow palpebral fissures, full cheeks, small nose with depressed nasal bridge, small and hypotonic mouth, irregular alignment of teeth, and bilateral microtia (Fig. 2). Both elbow and knee joints were hypermobile. Fingers IIeV had cutaneous syndactylies and webbing between the proximal and distal phalanges, “phalangeal pterygium” (Fig. 3). Besides bilateral clubfoot deformity the examination of the feet showed bilateral cutaneous syndactyly of toes II and III (Fig. 4). The thorax had an asymmetric shape and the mammillae were hypoplastic. Besides the genital malformation mentioned above (micropenis, bifid scrotum) an antepositioned anus and a sacral dimple were noted. He had muscular hypotonia.
3. Investigations All investigations including newborn metabolic screening and comprehensive genetic studies could not clarify the underlying cause of the syndromic condition. Analyses performed include routine karyotyping, biochemical investigations (7-dehydrocholesterol regarding SmitheLemlieOpitz syndrome, amino acids, organic acids in urine), and high resolution molecular karyotyping. Oligo microarray analysis using Agilent’s SurePrint G3 Human CGH Microarray Kit 2 400 K (Design ID 021850, Agilent, Santa Clara, CA, USA) revealed two copy number variations (CNV), one inherited from the unaffected father and the other from the unaffected mother: arr9q33.1 (119,318,986x2, 119,332,835119,361,232x1, 119,366,231x2)pat, arr11p15.1 (20,808,651x2, 20,804,606e20,969,024x3, 20,973,131x2)mat (GRCh37/hg19). The deleted region in 9q33.1 contains only intronic sequences of the ASTN2 gene. DECIPHER patient 259298 with the overlapping 9q33.1 deletion of 300 kb (phenotype not known) also inherited it from the unaffected parent. The duplication within subband 11p15.1 includes several exons of the NELL1 gene, which has so far not been associated with known intellectual disability syndromes. A biallelic mutation of NELL1 in mice leads to a complex phenotype including impaired development of the intervertebral discs, vertebrae, and calvarian bones, and perinatal lethality [3]. However, the duplication was also present in the mother who did not resemble a similar phenotype as her son. Moreover, a deletion of several exons of the NELL1 gene was observed within our own patient group, which was also inherited from the healthy parent. In summary, both aberrations are considered to be benign and unlikely to be of relevance for the phenotype [4]. 4. Discussion The main features of van Maldergem syndrome can be summarized as moderate to severe intellectual disability, hypotonia, distinctive combination of minor facial anomalies, finger camptodactyly, and joint hyperlaxity. Due to the facial dysmorphism and the additional malformations e especially regarding the hands with camptodactyly, syndactyly, and interphalangeal pterygium in the reported patient the diagnosis of van Maldergem syndrome was established. The similarity of his facial features to the two patients from the literature is very striking; also the skeletal (syndactyly and
Fig. 1. Cranial MRI scan taken of the patient at the age of 1 month, transverse (a) and coronal (b) T1-weighted sequences, showing hypoplasia of the corpus callosum.
T.M. Neuhann et al. / European Journal of Medical Genetics 55 (2012) 423e428
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Fig. 2. Patient at the age of 2 years and 10 month (a) and at the age of 4 years and 2 months. (b) Note hypotonic expressionless face, high frontal hairline, bilateral epicanthus, telecanthus, short palpebral fissures, depressed nasal bridge, short nose, open mouth appearance, dental malocclusion, and bilateral microtia.
camptodactyly, joint laxity, talipes) and neurological phenotype (hypotonia, intellectual disability) is very similar (Table 1). The patient presented here does show some additional features: he is the first male patient with this condition and had malformations of the external genitalia (micropenis, bifid scrotum, cryptorchidism); also, the boy had pharyngeal instability, bilateral inguinal hernias, and hip dysplasia. These features might also belong to the extended phenotype of van Maldergem syndrome. Since the parents of the patient are consanguineous, autosomal recessive inheritance is likely; however, autosomal dominant inheritance due to a novel mutation cannot be excluded. With a boy and two girls affected, X chromosomal inheritance seems less likely.
Since the phenotype of the patient is very distinct, only few differential diagnoses had enough overlapping features to be considered. These were evaluated by a search with different combinations of the minor and major anomalies present (“telecanthus”, “microtia “, ‘‘syndactyly”, “camptodactyly”, “club foot deformity”, “joint laxity”, “intellectual disability’’) which led to an extensive list of syndromic conditions. However, most of the possible differential diagnoses could be excluded based on the absence of specific features (e.g. Aarskog syndrome, ATRX syndrome, acrofacial dysostosis, SaethreeChotzen syndrome, SmitheLemlieOpitz syndrome).
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Fig. 3. Hands of the patient. Note cutaneous syndactyly and interphalangeal webbing.
4.1. Blepharo-naso-facial syndrome This condition was considered as a differential diagnosis by van Maldergem et al. [1]. Although some of the features overlap (telecanthus, syndactyly, joint laxity, intellectual
disability), these patients do not have the ear malformations and camptodactyly as seen in the patient described here. Also, some of the major features (lacrimal duct obstruction, extrapyramidal disorders) described in this condition [5e7] are absent in the reported patient which makes the diagnosis
Fig. 4. Feet of the patient at the age of 4 years and 2 months. The feet had been redressed due to bilateral clubfoot deformity since the first year of life. Additionally, there is cutaneous syndactyly of toes II and III.
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Table 1 Clinical features of the 3 patients with van Maldergem syndrome. Van Maldergem et al.
Zampino et al.
Present patient
Gender Age Height OFC Frontal hairline Telecanthusa Epicanthus Downslanting palpebral fissures Ptosis Dental malocclusion W-shaped upper lip Everted lower lip Macrostomia Downturned mouth Microtia/dysplastic ears Camptodactyly Syndactyly Talipes Joint hyperlaxity Hypotonia IDb Hyperkinesia Ataxia CNS malformation
F 11 y 50th centile 3rd centile Low D D D þ D D þ þ D D D D D D D Moderate þ e e
M 4y2m <3rd centile (2.1 SD) <3rd centile (2,5 SD) High D D D e D D e e D D D D/Interdigital pterygium D D D Severe e e Hypoplastic corpus callosum
Genital abnormalitiesc Pharyngeal dysfunction with feeding difficulties Hypoplastic kidneys
e e e
F 5y6m 75th centile 10th centile Low D D D þ D D þ þ D D D D D D D Severe þ þ Hypoplastic corpus callosum, cerebellar and pons hypoplasia e e e
a b c
þ þ þ
Overlapping features are highlighted in bold. ID e intellectual disability. New features in the patient described in this report are highlighted in italics.
of blepharo-naso-facial syndrome in the reported patient unlikely. 4.2. Hennekam syndrome Hennekam et al. [8] described a syndrome with unusual face that does resemble the facial dysmorphism of our patient and of the patients with van Maldergem syndrome from the literature; besides microtia the ocular and dental malformations are similar, also intellectual disability is a feature of Hennekam syndrome. However, camptodactyly and syndactyly, although been described [9], are not a consistent feature. Moreover, patients with Hennekam syndrome show a significant lymphedema e a feature that has not been observed in our patient nor the two published van Maldergem syndrome patients. 4.3. WintereTsukahara syndrome This syndrome has so far only been described in a few patients [10e12]. Again, the facial features do share similarities with the patients with van Maldergem syndrom and the present case. Also genital malformations and camptodacytly have been described. However, in these patients pachygyria is a common feature, which was not observed in the patients with van Maldergem syndrome. 4.4. EastmaneBixler syndrome This facio-cardio-renal syndrome was first described in 1977 [13]. Besides the facial features (telecanthus, microtia, dental anomalies), finger syndactyly, and genital malformations, this syndrome is further characterized by cleft palate, renal malformations (especially horseshoe kidney), and cardiac anomalies (endocardial fibroelastosis, conduction defects) [13e15]. The latter malformations are not present in our patient.
In conclusion, the presented case report further delineates the very characteristic entity of van Maldergem syndrome. The presented patient adds additional features to the phenotype such as genital malformation, and the clinical course of the condition e pharyngeal instability and feeding difficulties. Since both male and female patients are known and the parents of our patient are consanguineous, autosomal recessive inheritance is proposed. Acknowledgments We thank the family for their boundless cooperation. Furthermore, we would like to thank Dr. L. van Maldergem for confirming the diagnosis and Dr. M. Notohamiprodjo for his support regarding the MRI pictures. This work was supported by the Bundesministerium für Bildung und Forschung (BMBF) network grant MR-NET 01GS08166. References [1] L. van Maldergem, C. Wetzburger, A. Verloes, C. Fourneau, Y. Gillerot, Mental retardation with blepharo-naso-facial abnormalities and hand malformations: a new syndrome? Clin. Genet. 41 (1992) 22e24. [2] G. Zampino, C. Colosimo, F. Balducci, P. Mariotti, F. Serra, G. Scarano, P. Mastroiacovo, Cerebro-facio-articular syndrome of van Maldergem: confirmation of a new MR/MCA syndrome, Clin. Genet. 45 (1994) 140e144. [3] J. Desai, M.E. Shannon, M.D. Johnson, D.W. Ruff, L.A. Hughes, M.K. Kerley, D.A. Carpenter, D.K. Johnson, E.M. Rinchik, C.T. Culiat, Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects, Hum. Mol. Genet. 15 (2006) 1329e1341. [4] D.A. Koolen, R. Pfundt, N. de Leeuw, J.Y. Hehir-Kwa, W.M. Nillesen, I. Neefs, I. Scheltinga, E. Sistermans, D. Smeets, H.G. Brunner, A.G. van Kessel, J.A. Veltman, B.B. de Vries, Genomic microarrays in mental retardation: a practical workflow for diagnostic applications, Hum. Mutat. 30 (2009) 283e292. [5] J.E. Allanson, A second family with blepharo-naso-facial syndrome, Clin. Dysmorphol. 11 (2002) 191e194. [6] H. Pashayan, S. Pruzansky, A. Putterman, A family with blepharo-naso-facial malformations, Am. J. Dis. Child. 125 (1973) 389e393.
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