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2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragmatic hernia

Bermudez-Wagner, Karlaa; Jeng, Linda J.B.b; Slavotinek, Anne M.a; Sanford, Erica F.a

Author Information
doi: 10.1097/MCD.0b013e32835b8df2
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List of key features

  • Morgagni diaphragmatic hernia
  • Developmental delays
  • Hypotonia
  • Short stature
  • Ptosis
  • Wide mouth
  • Brachydactyly
  • Nail hypoplasia

Short clinical summary

The proposita was the product of a 31-week monochorionic–diamniotic twin pregnancy to a 30-year-old G5P1 woman. The pregnancy was complicated by pre-eclampsia at 18 weeks of gestation. Delivery was by Cesarean section for premature rupture of membranes. Her twin sister died at 28 days with necrotizing enterocolitis. The proposita’s medical history comprised a Morgagni-type diaphragmatic defect, patent ductus arteriosus, and an umbilical hernia that were all surgically repaired, failure to thrive, gastrointestinal reflux disease, astigmatism, asthma, and recurrent otitis media requiring tympanostomy tubes. She sat unsupported at 12 months and walked at 2 years of age. She said her first words at 1 year and used phrases between 30 and 36 months of age. At 8 years of age, she was 6–18 months behind her peers.

On examination at 8 years of age (Fig. 1), her height was 108 cm (<3rd centile; 50th centile for a 5–6-year-old girl), weight was 16.8 kg (<3rd centile; 50th centile for a 5-year-old girl), and head circumference was 47 cm (<3rd centile; 50th centile for an 18-month-old girl). She had plagiocephaly, bilateral ptosis with downslanting palpebral fissures, a long nose with anteverted nares, a smooth philtrum, and a wide mouth with a thin upper lip and a high palate. There were dimples on both lateral gluteal areas and the sacral area. Her hands showed brachydactyly (third finger length 4.9 cm; <3rd percentile), clinodactyly of the fifth fingers with a single crease on each fifth finger, and nail hypoplasia. Her feet indicated hallux valgus, small second toes, and nail hypoplasia. She showed hypotonia and hyperreflexia, poor coordination and balance, and halting speech.

Fig. 1
Fig. 1:
(a) The face of the proband at 9 years of age. Note the long face, slightly high anterior hairline, bilateral ptosis with downslanting palpebral fissures, long eyelashes, long and relatively narrow nose with anteverted nares, smooth philtrum, relatively large mouth with thin lips, and mild mandibular prognathism with retrognathia. (b) The hands and feet of the proband. She had small hands with short fingers, broad fingertips, and fifth finger brachydactyly with absence of the distal creases on both fifth fingers. She had small feet with brachydactyly of the second toes and dysplastic nails.

The proposita’s father was diagnosed with attention deficit hyperactivity disorder and cognitive difficulties early in life, but he did well with special education and later completed a college degree. He had obesity, sleep apnea, left ventricular cardiomyopathy, severe asthma, astigmatism, and left-sided esotropia. A paternal great-aunt and her son reportedly had mental retardation. The proposita had a healthy 12-year-old sister. Consanguinity was denied.


A karyotype showed normal female chromosomes (46,XX). Growth hormone studies, thyroid studies, testing for celiac disease, and cystic fibrosis were unrevealing. A head computed tomography scan was reportedly normal at birth. Array comparative genomic hybridization using a 105K-featured whole-genome microarray (Signature Select version 1.1; custom-designed by Signature Genomics, Spokane, Washington, USA; made by Agilent Technologies, Santa Clara, California, USA) showed an interstitial deletion between 0.189 and 0.332 Mb in size at chromosome 2p16.3 (chr2: 50,890,607–51,079,734)x1 (hg18) (Fig. 2). This region contains a single OMIM gene, NRXN1, and the deletion removed exons 4, 5, and 6 of the gene (transcript NG_011878.1). Targeted array analysis carried out in both parents indicated that the deletion was inherited from the proposita’s father.

Fig. 2
Fig. 2:
Microarray characterization of a 2p16.3 deletion. Microarray plot showing single-copy loss of four oligonucleotide probes from the short arm of chromosome 2 at 2p16.3, ∼190 kb in size (chr2: 50,890,607–51,079,734, genome build hg18). Probes are ordered on the x-axis according to physical mapping positions, with the most distal 2p16.3 probes to the left and the most proximal 2p16.3 probes to the right. Values along the y-axis represent log2 ratios of patient : control signal intensities. NRXN1 transcripts, as annotated in the Reference Sequence database, are represented as blue bars, with the light blue segments representing exons. Results are visualized using Genoglyphix (Signature Genomics).


This patient is of interest because her presentation includes dysmorphic features, short stature with microcephaly, hypotonia, and a persistent patent ductus arteriosus in addition to the global developmental delays associated previously with exonic deletions of NRXN1 (Schaaf et al., 2012). There are no other reports of diaphragmatic hernia in similar deletion patients, and mouse models of loss of neurexin function have not shown this birth defect (Südhof, 2008; Etherton et al., 2009; Ching et al., 2010; Schaaf et al., 2012). Anteromedial (Morgagni) diaphragmatic hernias have been described in dizygotic twins (Lau et al., 2005), and we cannot be certain that this finding is a direct consequence of the NRXN1 deletion.

Although there is no characteristic physical phenotype associated with NRXN1 deletions, a retrospective record review of 12 children with NRXN1 deletions of 65 kb to 5 Mb in size showed that two patients had ventricular septal defects (Ching et al., 2010). In a subsequent review of 17 patients with exonic deletions of NRXN1, complex congenital heart disease was present in one child who had an additional duplication of 17p12, whereas another male had pulmonary hypoplasia, omphalocele, bilateral talipes, and scoliosis (Schaaf et al., 2012). Vertebral anomalies comprising fusion of T2, T3, T4, L4, and L5 vertebral bodies with an extra left rib and a bifid second rib have also been reported (Zahir et al., 2008). Other musculoskeletal abnormalities associated with NRXN1 deletions included plagiocephaly, prominent coronal sutures, delayed closure of the anterior fontanel, incomplete fusion of the ring of the first cervical vertebrae, Poland anomaly, hip dysplasia, clinodactyly, small feet and curved toes, and VATER/VACTERL association (Ching et al., 2010).

The proband’s father had the same NRXN1 deletion, but was less affected than his offspring and he was not dysmorphic. Dysfunction of neurexins hinders the ability of synapses to refine and transmit signals between neurons, but does not completely impair synaptic transmission (Reissner et al., 2008; Südhof, 2008). This subtlety makes it possible for individuals with the same deletion or mutation, even if from the same family, to show very different phenotypes.


The authors are indebted to the family who participated in this study.

Conflicts of interest

There are no conflicts of interest.


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