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. Author manuscript; available in PMC: 2022 May 13.
Published in final edited form as: Clin Dysmorphol. 2015 Apr;24(2):65–67. doi: 10.1097/MCD.0000000000000063

Small bowel malrotation in distal 15q duplication: evidence for a rare association

Brooke M McLaughlin a, Robert B Hufnagel b, Howard M Saal a,b
PMCID: PMC9100852  NIHMSID: NIHMS1693523  PMID: 25415058

Clinical summary

The patient is a 3-year 11-month-old white male. His care was transferred to our facility for management and treatment of his complex gastrointestinal issues. Physical examination revealed a weight of 18.9 kg (+ 2.289 SD), length of 111.8 cm (+ 4.762 SD), and a head circumference of 49 cm (− 2.157 SD). Dysmorphic features include a turricephaly with tapering high forehead, long philtrum, up-slanting palpebral fissures, low-set ears, bulbous nasal tip, micrognathia, ptosis (Fig. 1a and b), bifid uvula, submucous cleft palate, narrow chest with widely spaced nipples, pectus excavatum, arachnodactyly, and overlapping of the second and third toes. A computed tomography scan with three-dimensional reconstruction demonstrated sagittal craniosynostosis (Fig. 1c and d). His echocardiogram and audiogram were normal. He had developmental delays and started sitting unsupported at 26 months and started walking at 27 months. He had age-appropriate fine motor skills but was unable to dress himself. He was socially interactive and attentive but had tendencies to be ritualistic with activities. He had speech apraxia and was nonverbal, communicating primarily with sign language. He was able to follow multistep commands.

Fig. 1.

Fig. 1

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(a–d) Characteristic facial dysmorphism associated with 15q duplication syndrome, including sagittal craniosynostosis (c, d: three-dimensional computed tomography reconstruction).

The patient was born by spontaneous vaginal delivery at 36 weeks gestation to a healthy 30-year-old G2P1 woman. The pregnancy was uncomplicated, with normal ultrasounds and serum screens for aneuploidy. Birth weight was 3.797 kg (+ 3.376 SD), birth length was 53 cm (+ 3.773 SD), and head circumference was 34.5 cm (+ 1.988 SD). At 3 weeks of life, he had unresolved jaundice (bilirubin level 17). Anatomical evaluation revealed a horseshoe kidney, bilateral inguinal hernias, pyloric stenosis, and small intestine malrotation. He underwent a pyloromyotomy, Ladd’s procedure, and appendectomy. At 6.5 months of age, he underwent bifrontal, parietal, and occipital craniotomy with posterior cranial vault remodeling for congenital sagittal synostosis. At 1 year of age, he required bilateral myringotomies and pressure-equalizing tubes for recurrent otitis media. He has had febrile seizures beginning at 1 year of age to present. At 3 years of age, he was hospitalized for persistent vomiting and was found to have gastroparesis based on a gastric emptying scan (10%; normal range 44–58%), which improved after treatment with erythromycin ethylsuccinate. At 3.5 years of age, he was hospitalized again for vomiting and treated with a pyloric balloon dilatation and gastrostomy tube placement.

Family history was significant for horseshoe kidney in one identical twin paternal aunt. There was no family history for congenital anomalies, developmental nor intellectual disabilities, recurrent pregnancy loss, stillbirth, infant death, nor consanguinity.

Laboratory studies

SNP microarray analysis was performed using the hybridized Affymetrix Cytoscan HD GeneChip and Chromosome Analysis Suite (Affymetrix, Santa Clara, California, USA). A 3.61 Mb terminal deletion at 12p13.32-terminus [12p13.33p13.32 (191 242–3 614 555)×1, CRCh37/hg19] and a 14.49 Mb terminal duplication at 15q25.3-terminus [15q25.3q26.3 (88 042 642–102 429 112) × 3, CRCh37/hg19], including the IGF1R gene, were detected (Integrated Genetics, Santa Fe, New Mexico, USA). Cytogenetic analysis of his peripheral blood confirmed an unbalanced translocation, revealing the expected karyotype, 46,XY,der (12)t(12;15)(p13;q25) (LabCorp, Tyler, Texas, USA). Parents declined chromosome testing.

Discussion

Distal duplications of 15q have been reported in 71 other patients (Gutiérrez-Franco Mde et al., 2010). Most reported cases were associated with parental reciprocal balanced translocations such that deletions of other chromosomes were commonly seen with 15q duplication. Thus, it is difficult to establish which clinical features can be specifically attributed to the 15q trisomy or the other chromosomal monosomy. Consistent features of distal chromosome 15q duplications include prenatal and postnatal overgrowth in 71% of cases (attributed to overexpression of the IGF1R gene) (Faivre et al., 2002), mild to severe intellectual disability in 100% of cases, and craniofacial malformations in 94% of cases, including craniosynostosis, microcephaly, high frontal hairline, bitemporal narrowing, ptosis, down-slanting palpebral fissures, broad nasal bridge, long philtrum, high-arched palate, low-set ears, micrognathia, and short neck (Tatton-Brown et al., 2009; Puvabanditsin et al., 2013).

Other reported features are ocular anomalies (coloboma and strabismus), pectus excavatum, malformations of fingers and toes (arachnodactyly, camptodactyly, shortened thumb, broad first toe), cryptorchidism, cardiac defects (patent ductus arteriosus and aortic stenosis), renal anomalies (horseshoe kidney, unilateral renal agenesis, hydronephrosis, vesicoureteral reflux, polycystic kidney, right pelvic duplication), sensorineural hearing loss, and pulmonary hypoplasia (Tatton-Brown et al., 2009; Puvabanditsin et al., 2013).

Distal 12p deletions have been reported in at least 20 cases (Lagier-Tourenne et al., 2004) and have an indistinct and variable phenotype. Features include prenatal and postnatal growth delay, developmental and speech delay, schizophrenia, autism, febrile seizures, microcephaly, facial asymmetry, malformed/low-set ears, hearing loss, hypertrophic gums, inguinal hernia, hypertonia, arachnodactyly, and camptodactyly (Glass et al., 2000; Vargas et al., 2012). Pyloric stenosis, gastroparesis, and intestinal malrotation have not been reported in patients with distal 12p deletion.

The majority of our patient’s features have been identified in patients with distal 15q duplication and distal 12p deletion. Features associated with distal 15q duplication include postnatal overgrowth, intellectual disability, craniofacial malformation (craniosynostosis, microcephaly, ptosis, long philtrum, high-arched palate, low-set ears, and micrognathia), pectus excavatum, arachnodactyly, and renal anomalies (horseshoe kidney). Features observed in our patient and patients with distal 12p deletion are less specific and include developmental delay, febrile seizures, microcephaly, low-set ears, inguinal hernia, and arachnodactyly.

Intestinal malformations as seen in our patient (pyloric stenosis, gastroparesis, and malformation) have been rarely documented in patients with 15q duplication but not 12p deletion. Three cases with mosaic trisomy 15 (Bleyl et al., 2007), unbalanced 5p;15q translocation (Puvabanditsin et al., 2013), and ring duplicated chromosome 15 (Otto et al., 1984) have been reported with intestinal malrotation. A single report documented an unbalanced translocation involving 12p and 15q with a karyotype of 46,XY,der(12),t (12;15)(p13;q25), similar to our patient (Pedersen, 1976), though only distinct facial features and intellectual disability were reported. There are three case reports for intestinal malrotation associated with overexpression of distal 12p (Baglaj et al., 2008; Pini Prato et al., 2011; Al-Hertani et al., 2012). However, there are no reports of distal 12p deletion with intestinal malrotation.

To our knowledge, this is the fourth case of partial chromosome 15 duplication with intestinal malrotation and the first case of an unbalanced 12p;15q translocation with intestinal malrotation. This finding refines the 15q duplication critical region associated with intestinal malrotation to 15q23-ter, suggesting overexpression of genes within this region confer increased susceptibility for intestinal malrotation. Patients with this significant malformation warrant investigation for chromosomal abnormalities. Further study is warranted to investigate the development and natural history of intestinal malrotation associated with distal 15q duplication.

In summary, we report newly recognized phenotypes associated with distal 15q duplication. Given previous reports of mosaic trisomy 15 and partial trisomy 15, intestinal malformations are best explained by the distal 15q duplication, specifically the newly identified critical region 15q23-ter. Infants with distal 15q duplication should be evaluated for gastrointestinal anomalies at the time of diagnosis and providers should strongly consider chromosomal abnormalities on the differential diagnosis for infants with this spectrum of gastrointestinal malformation.

Acknowledgements

The authors thank the family of our patient for allowing us to publish clinical details and photographs.

Footnotes

Conflicts of interest

There are no conflicts of interest.

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