Short case report 75
A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1 Peter Holmquist Clinical Dysmorphology 2015, 24:75–78
Tel: + 46 46 17 10 00; e-mail: [email protected]
Department of Paediatrics, Skåne University Hospital, Lund, Sweden
Received 2 May 2014 Accepted 11 November 2014
Correspondence to Peter Holmquist, MD, Department of Paediatrics, Skåne University Hospital, Lund 22185, Sweden
List of key features Dysmorphic features Intellectual disability Failure to thrive
Introduction In humans, three neurexin genes are involved in coordinating presynaptic and postsynaptic neuroligin activity by altering Ca2 + -dependent neurotransmittor release within the central nervous system, essential to create cognitive function. Each gene has two promoters forming α and β neurexins with many isoforms (Ullrich et al., 1995). Heterozygous defects in NRXN1 have been reported to be risk factors for neuropsychiatric disorders (Ching et al., 2010; Wiśniowiecka-Kowalnik et al., 2010; Gregor et al., 2011). MRI scans in patients with heterozygous NRXN1 defects are mostly normal (Ching et al., 2010), but can also show cyst formation and atrophy in the hippocampus (Duong et al., 2012). Exonic deletions with variable phenotype and penetrance have been Table 1
associated with intellectual disability, mild abnormal behaviors, and mild dysmorphic features (Béna et al., 2013; Dabell et al., 2013). Patients with biallelic defects are rare, but three previous studies have identified four patients with biallelic, compound heterozygous defects in NRXN1, and their phenotypic features are summarized in Table 1 (Zweier et al., 2009; Harrison et al., 2011; Duong et al., 2012). A further patient with a biallelic homozygous deletion in NRXN1 is reported here.
Case report The patient is the fifth child to consanguineous MiddleEastern parents who are first cousins. The parents, three older sisters, and a brother are all healthy and without symptoms. No other illnesses are known within the family. The patient was born at gestational week 34 + 4 days by emergency Cesarean section because of threatening asphyxia (Apgar score 3–6–8 at 1–5–10 min). His birth weight was 2458 g. Because of prematurity and transient
Phenotype in patients with biallelic NRXN1 defects
Patient NRXN1 del Age (years) Sex Developmental delay Seizures Social interaction Age walking MRI-scan
Breathing abnormality Hypotonia Speech Stereotypies Strabismus Hearing impairment Failure to thrive Dysmorphic features Other
Duong et al. (2012)
New patient 170 + 170 kbp
451 kbp
Zweier et al. (2009)
Harrison et al. (2011) Sibling 1
Harrison et al. (2011) Sibling 2
180 kbp 18 Female Severe
79 + 287 kbp 16 Female Severe
79 + 287 kbp 11 Female Severe
Yes Lacing 3 years Atrophy, cysts deflecting the right hippocampus
No Lacing 2 years Normal
Yes Limited 5 years Normal
Yes Limited Not able Normal
No
Yes
Yes
Yes
Yes No Yes Yes Yes Yes Yes
Yes No Yes Yes Yes No Yes
No No Yes Yes No No Yes
Yes Words Yes No No Yes No
Yes No Yes No No Yes No
Undescended testis, increased aminotransferase levels, highpitched cry
Autistic traits, excessive salivation
Hypermotoric behavior, excessive salivation
Scoliosis, early puberty, constipation, pulmonary stenosis
Scoliosis, early puberty, constipation, pulmonary stenosis
4 Male Severe
33 Male Severe
No Lacing Not able Thin cerebral white matter, periventricular high T2 signals, expanded Virchow–Robin spaces No
0962-8827 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MCD.0000000000000070
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
76 Clinical Dysmorphology 2015, Vol 24 No 2
Fig. 1
Photograph at 4 years of age shows microcephaly, micrognathia, puffy hands and feet, thick and elastic skin, medial strabismus on the right eye, lowset large ears, a beaked nose, and a curved fifth finger.
tachypnea, he was transferred to the neonatal ICU, where a medical examination indicated a high-arched palate, bilateral undescended testis, palmar crease in his right hand, a high-pitched cry, low-set large ears with soft cartilage, a beaked nose, curved fifth fingers, and preauricular appendages. He developed prolonged hypoglycemia (plasma glucose 0.5–3.0 mmol/l) and had a sustained elevated base deficit (>3.0 mEq/l). Thyroid-stimulating hormone (TSH) measured 90 mIE/l (neonatal screening cutoff value 35 mIE/l), and he had a low ionized calcium (< 1.05 mmol/l). He was treated with sodium bicarbonate, thyroid hormone supplement, and calcium lactate. After 1 month, while still on the above therapy, laboratory tests for blood glucose, ionized calcium, TSH, 17-hydroxysteroids, plasma ammonium, thyroid antibodies, vitamin D, serum aminotransferases, plasma amino acids, and urine organic acids were normal. Since 4 months of age,
serum aminotransferases have been elevated, but the patient has had no abdominal problems, and abdominal ultrasound exams were normal. Sodium bicarbonate and calcium lactate were discontinued after 1 year and thyroid hormone supplementation after 3 years. The patient has been fed solely formula milk (Infantrini, later Nutrini) through his first years because of persistent failure to thrive. His constantly swollen hands and feet have been less puffy since Nutrini was stopped. He still cannot feed himself and all food has to be liquidized. At the age of 4 years, he has no medication, his bilateral inguinal hernias have been operated, and his testis has been fixed in the scrotum. His head circumference measures 46 cm (− 4SD) and has only increased 1 cm since 18 month of age. His weight (13.5 kg) and height (96 cm) continue along − 2SD on a standard Swedish growth chart.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Homozygous biallelic deletion in NRXN1 Holmquist 77
Fig. 2
a thick and elastic skin, and strabismus of the right eye. Some of these features are shown in Fig. 1. He has severe intellectual disability with no speech and no social performance. He is mostly silent, but sometimes presents monotonic noises. When instructed, he may clap his hands. He prefers to sit in his wheel chair with limited facial or a slightly anxious expression, but is easily upset or frightened and has a high-pitched cry, tremor, bodyrocking, and head banging or stereotypic hand and arm movements. When comforted by the family members, this behavior quickly subsides. His MRI-scan shows slight thinning of cerebral white matter, periventricular high T2 signals particularly in the back parts of centrum semiovale bilaterally, and expanded Virchow–Robin spaces (Fig. 2). Morphology, cerebral gray matter, basal ganglia, hypothalamus–pituitary axis, and myelination of the brain were normal for age. Complete body skeleton radiography and MR-spectroscopy (single-voxel technique) were normal. Repeated echocardiograms were unremarkable. Genetic investigation
The patient’s karyotype is normal and an early metaphase-fluorescence in situ hybridization analysis excluded 22q11.2 deletion. On array comparative genomic hybridization (array CGH; Karolinska Institute, Stockholm, Sweden), a 170 kbp intronic homozygous deletion in NRXN1 (Wiśniowiecka-Kowalnik et al., 2010) (p16.3p16.3) was discovered. The patient’s parents and three sisters, but not his brother, are heterozygous carriers of the deletion as detected by multiplex ligation probedependent amplification (MLPA; Karolinska Institute, Stockholm, Sweden). The location and breakpoints of the deletion within the NRXN1 are chr2 : 50,725,329-50,890,429 (min. deleted region, hg18), and chr2 : 50,704,277-50,911,152 (max. deleted region, hg18).
MRI scan with slightly thin cerebral white matter, periventricular high T2 signals particularly in the back parts of the centrum semiovale bilaterally (a), and expanded Virchow–Robin spaces (b).
His motor development has been very slow, and he is unable to walk, but can sit and roll from place to place. He grabs and holds onto things. There have been no seizures and repeated electroencephalograms have been normal. Bilateral hearing aids, prescribed because of reduced hearing, were withdrawn because of negative reactions to high sounds. In addition to the previously described dysmorphic facial and body features, he also has microcephaly, micrognathia,
This analysis does not indicate the absence of any coding sequence; however, aberrant splicing of the gene cannot be excluded. The NCBI Reference Sequence database includes only a few representative transcript variants and according to this, the minimum region does not contain a described exon, whereas the maximum region contains exon 6 in mRNA NM_001135659.1. In the Ensembl Genome Browser database, there are three exons in the minimum region, but they are possibly just ‘predicted’. Conclusion
No other family member apart from the patient has a biallelic homozygous 170 kbp deletion in NRXN1. The deletion is predicted to be wholly intronic and does not affect exons in NRXN1; therefore, its pathogenic relevance is not fully clarified. The possibility remains that it is associated with the phenotype. In accordance with other
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
78 Clinical Dysmorphology 2015, Vol 24 No 2
reports, the findings of sustained low ionized calcium, elevated TSH, and serum aminotransferase levels might suggest a link to somatic endocrine and gastrointestinal conditions (Harrison et al., 2011; Duong et al., 2012). In the case described here, the family is consanguineous in contrast to the three families previously reported with biallelic NRXN1 defects (Zweier et al., 2009; Harrison et al., 2011; Duong et al., 2012). This raises the possibility that an alternative recessive condition may be responsible for some or all the patient’s features. Further tests are needed to fully clarify whether this deletion affects gene expression and may be linked to the phenotype. This could not be done unfortunately within the context of this report, but the clinical description and details of the deletion could be valuable for future genotypic and phenotypic delineation of the NRXN1 phenotype.
Acknowledgements Parental written consent to use photographic material has been obtained. Conflicts of interest
There are no conflicts of interest.
References Béna F, Bruno DL, Eriksson M, van Ravenswaaij-Arts C, Stark Z, Dijkhuizen T, et al. (2013). Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. Am J Med Genet B Neuropsychiatr Genet 162B:388–403. Ching MSL, Shen Y, Tan W-H, Jeste S, Morrow EM, Chen X, et al. Children’s Hospital Boston Genotype Phenothype Study Group (2010). Deletions of NRXN1 (Neurexin-1) predispose to a wide spectrum of developmental disorders. AM J Med Genet B Neuropsychiatr Genet 153:937–947. Dabell MP, Rosenfeld JA, Bader P, Escobar LF, El-Khechen D, Vallee SE, et al. (2013). Investigation of NRXN1 deletions: clinical and molecular characterization. Am J Med Genet A 161A:717–731. Duong L, Klitten LL, Møller RS, Ingason A, Jakobsen KD, Skjødt C, et al. (2012). Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders. Am J Med Genet B Neuropsychiatr Genet 159B:354–358. Gregor A, Albrecht B, Bader I, Bijlsma EK, Ekici AB, Engels H, et al. (2011). Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med Genet 12:106–118. Harrison V, Connell L, Hayesmoore J, McParland J, Pike MG, Blair E (2011). Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am J Med Genet A 155A:2826–2831. Ullrich B, Ushkaryov YA, Südhof TC (1995). Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14:497–507. Wiśniowiecka-Kowalnik B, Nesteruk M, Peters S, Xia Z, Cooper CL, Duda AW III, et al. (2010). Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay. Am J Med Genet B Neuropsychiatr Genet 153:983–993. Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, Collins AL, et al. (2009). CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 85:655–666.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1 Peter Holmquist Clinical Dysmorphology 2015, 24:75–78
Tel: + 46 46 17 10 00; e-mail: [email protected]
Department of Paediatrics, Skåne University Hospital, Lund, Sweden
Received 2 May 2014 Accepted 11 November 2014
Correspondence to Peter Holmquist, MD, Department of Paediatrics, Skåne University Hospital, Lund 22185, Sweden
List of key features Dysmorphic features Intellectual disability Failure to thrive
Introduction In humans, three neurexin genes are involved in coordinating presynaptic and postsynaptic neuroligin activity by altering Ca2 + -dependent neurotransmittor release within the central nervous system, essential to create cognitive function. Each gene has two promoters forming α and β neurexins with many isoforms (Ullrich et al., 1995). Heterozygous defects in NRXN1 have been reported to be risk factors for neuropsychiatric disorders (Ching et al., 2010; Wiśniowiecka-Kowalnik et al., 2010; Gregor et al., 2011). MRI scans in patients with heterozygous NRXN1 defects are mostly normal (Ching et al., 2010), but can also show cyst formation and atrophy in the hippocampus (Duong et al., 2012). Exonic deletions with variable phenotype and penetrance have been Table 1
associated with intellectual disability, mild abnormal behaviors, and mild dysmorphic features (Béna et al., 2013; Dabell et al., 2013). Patients with biallelic defects are rare, but three previous studies have identified four patients with biallelic, compound heterozygous defects in NRXN1, and their phenotypic features are summarized in Table 1 (Zweier et al., 2009; Harrison et al., 2011; Duong et al., 2012). A further patient with a biallelic homozygous deletion in NRXN1 is reported here.
Case report The patient is the fifth child to consanguineous MiddleEastern parents who are first cousins. The parents, three older sisters, and a brother are all healthy and without symptoms. No other illnesses are known within the family. The patient was born at gestational week 34 + 4 days by emergency Cesarean section because of threatening asphyxia (Apgar score 3–6–8 at 1–5–10 min). His birth weight was 2458 g. Because of prematurity and transient
Phenotype in patients with biallelic NRXN1 defects
Patient NRXN1 del Age (years) Sex Developmental delay Seizures Social interaction Age walking MRI-scan
Breathing abnormality Hypotonia Speech Stereotypies Strabismus Hearing impairment Failure to thrive Dysmorphic features Other
Duong et al. (2012)
New patient 170 + 170 kbp
451 kbp
Zweier et al. (2009)
Harrison et al. (2011) Sibling 1
Harrison et al. (2011) Sibling 2
180 kbp 18 Female Severe
79 + 287 kbp 16 Female Severe
79 + 287 kbp 11 Female Severe
Yes Lacing 3 years Atrophy, cysts deflecting the right hippocampus
No Lacing 2 years Normal
Yes Limited 5 years Normal
Yes Limited Not able Normal
No
Yes
Yes
Yes
Yes No Yes Yes Yes Yes Yes
Yes No Yes Yes Yes No Yes
No No Yes Yes No No Yes
Yes Words Yes No No Yes No
Yes No Yes No No Yes No
Undescended testis, increased aminotransferase levels, highpitched cry
Autistic traits, excessive salivation
Hypermotoric behavior, excessive salivation
Scoliosis, early puberty, constipation, pulmonary stenosis
Scoliosis, early puberty, constipation, pulmonary stenosis
4 Male Severe
33 Male Severe
No Lacing Not able Thin cerebral white matter, periventricular high T2 signals, expanded Virchow–Robin spaces No
0962-8827 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MCD.0000000000000070
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
76 Clinical Dysmorphology 2015, Vol 24 No 2
Fig. 1
Photograph at 4 years of age shows microcephaly, micrognathia, puffy hands and feet, thick and elastic skin, medial strabismus on the right eye, lowset large ears, a beaked nose, and a curved fifth finger.
tachypnea, he was transferred to the neonatal ICU, where a medical examination indicated a high-arched palate, bilateral undescended testis, palmar crease in his right hand, a high-pitched cry, low-set large ears with soft cartilage, a beaked nose, curved fifth fingers, and preauricular appendages. He developed prolonged hypoglycemia (plasma glucose 0.5–3.0 mmol/l) and had a sustained elevated base deficit (>3.0 mEq/l). Thyroid-stimulating hormone (TSH) measured 90 mIE/l (neonatal screening cutoff value 35 mIE/l), and he had a low ionized calcium (< 1.05 mmol/l). He was treated with sodium bicarbonate, thyroid hormone supplement, and calcium lactate. After 1 month, while still on the above therapy, laboratory tests for blood glucose, ionized calcium, TSH, 17-hydroxysteroids, plasma ammonium, thyroid antibodies, vitamin D, serum aminotransferases, plasma amino acids, and urine organic acids were normal. Since 4 months of age,
serum aminotransferases have been elevated, but the patient has had no abdominal problems, and abdominal ultrasound exams were normal. Sodium bicarbonate and calcium lactate were discontinued after 1 year and thyroid hormone supplementation after 3 years. The patient has been fed solely formula milk (Infantrini, later Nutrini) through his first years because of persistent failure to thrive. His constantly swollen hands and feet have been less puffy since Nutrini was stopped. He still cannot feed himself and all food has to be liquidized. At the age of 4 years, he has no medication, his bilateral inguinal hernias have been operated, and his testis has been fixed in the scrotum. His head circumference measures 46 cm (− 4SD) and has only increased 1 cm since 18 month of age. His weight (13.5 kg) and height (96 cm) continue along − 2SD on a standard Swedish growth chart.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Homozygous biallelic deletion in NRXN1 Holmquist 77
Fig. 2
a thick and elastic skin, and strabismus of the right eye. Some of these features are shown in Fig. 1. He has severe intellectual disability with no speech and no social performance. He is mostly silent, but sometimes presents monotonic noises. When instructed, he may clap his hands. He prefers to sit in his wheel chair with limited facial or a slightly anxious expression, but is easily upset or frightened and has a high-pitched cry, tremor, bodyrocking, and head banging or stereotypic hand and arm movements. When comforted by the family members, this behavior quickly subsides. His MRI-scan shows slight thinning of cerebral white matter, periventricular high T2 signals particularly in the back parts of centrum semiovale bilaterally, and expanded Virchow–Robin spaces (Fig. 2). Morphology, cerebral gray matter, basal ganglia, hypothalamus–pituitary axis, and myelination of the brain were normal for age. Complete body skeleton radiography and MR-spectroscopy (single-voxel technique) were normal. Repeated echocardiograms were unremarkable. Genetic investigation
The patient’s karyotype is normal and an early metaphase-fluorescence in situ hybridization analysis excluded 22q11.2 deletion. On array comparative genomic hybridization (array CGH; Karolinska Institute, Stockholm, Sweden), a 170 kbp intronic homozygous deletion in NRXN1 (Wiśniowiecka-Kowalnik et al., 2010) (p16.3p16.3) was discovered. The patient’s parents and three sisters, but not his brother, are heterozygous carriers of the deletion as detected by multiplex ligation probedependent amplification (MLPA; Karolinska Institute, Stockholm, Sweden). The location and breakpoints of the deletion within the NRXN1 are chr2 : 50,725,329-50,890,429 (min. deleted region, hg18), and chr2 : 50,704,277-50,911,152 (max. deleted region, hg18).
MRI scan with slightly thin cerebral white matter, periventricular high T2 signals particularly in the back parts of the centrum semiovale bilaterally (a), and expanded Virchow–Robin spaces (b).
His motor development has been very slow, and he is unable to walk, but can sit and roll from place to place. He grabs and holds onto things. There have been no seizures and repeated electroencephalograms have been normal. Bilateral hearing aids, prescribed because of reduced hearing, were withdrawn because of negative reactions to high sounds. In addition to the previously described dysmorphic facial and body features, he also has microcephaly, micrognathia,
This analysis does not indicate the absence of any coding sequence; however, aberrant splicing of the gene cannot be excluded. The NCBI Reference Sequence database includes only a few representative transcript variants and according to this, the minimum region does not contain a described exon, whereas the maximum region contains exon 6 in mRNA NM_001135659.1. In the Ensembl Genome Browser database, there are three exons in the minimum region, but they are possibly just ‘predicted’. Conclusion
No other family member apart from the patient has a biallelic homozygous 170 kbp deletion in NRXN1. The deletion is predicted to be wholly intronic and does not affect exons in NRXN1; therefore, its pathogenic relevance is not fully clarified. The possibility remains that it is associated with the phenotype. In accordance with other
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
78 Clinical Dysmorphology 2015, Vol 24 No 2
reports, the findings of sustained low ionized calcium, elevated TSH, and serum aminotransferase levels might suggest a link to somatic endocrine and gastrointestinal conditions (Harrison et al., 2011; Duong et al., 2012). In the case described here, the family is consanguineous in contrast to the three families previously reported with biallelic NRXN1 defects (Zweier et al., 2009; Harrison et al., 2011; Duong et al., 2012). This raises the possibility that an alternative recessive condition may be responsible for some or all the patient’s features. Further tests are needed to fully clarify whether this deletion affects gene expression and may be linked to the phenotype. This could not be done unfortunately within the context of this report, but the clinical description and details of the deletion could be valuable for future genotypic and phenotypic delineation of the NRXN1 phenotype.
Acknowledgements Parental written consent to use photographic material has been obtained. Conflicts of interest
There are no conflicts of interest.
References Béna F, Bruno DL, Eriksson M, van Ravenswaaij-Arts C, Stark Z, Dijkhuizen T, et al. (2013). Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. Am J Med Genet B Neuropsychiatr Genet 162B:388–403. Ching MSL, Shen Y, Tan W-H, Jeste S, Morrow EM, Chen X, et al. Children’s Hospital Boston Genotype Phenothype Study Group (2010). Deletions of NRXN1 (Neurexin-1) predispose to a wide spectrum of developmental disorders. AM J Med Genet B Neuropsychiatr Genet 153:937–947. Dabell MP, Rosenfeld JA, Bader P, Escobar LF, El-Khechen D, Vallee SE, et al. (2013). Investigation of NRXN1 deletions: clinical and molecular characterization. Am J Med Genet A 161A:717–731. Duong L, Klitten LL, Møller RS, Ingason A, Jakobsen KD, Skjødt C, et al. (2012). Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders. Am J Med Genet B Neuropsychiatr Genet 159B:354–358. Gregor A, Albrecht B, Bader I, Bijlsma EK, Ekici AB, Engels H, et al. (2011). Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med Genet 12:106–118. Harrison V, Connell L, Hayesmoore J, McParland J, Pike MG, Blair E (2011). Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am J Med Genet A 155A:2826–2831. Ullrich B, Ushkaryov YA, Südhof TC (1995). Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14:497–507. Wiśniowiecka-Kowalnik B, Nesteruk M, Peters S, Xia Z, Cooper CL, Duda AW III, et al. (2010). Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay. Am J Med Genet B Neuropsychiatr Genet 153:983–993. Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, Collins AL, et al. (2009). CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 85:655–666.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
