A de novo chromosome 9p duplication in a female child with short stature and developmental delay

Introduction

Chromosomal abnormalities represent a significant cause of developmental delay and intellectual disabilities, especially in the context of dysmorphic physical features and multiple congenital anomalies. Chromosome 9p duplication is one of the most commonly described autosomal partial trisomies known to be the fourth in frequency after the full trisomy 21, 13, and 18. ¹ The reason behind the compatibility with survival could be a relatively poor gene content in the affected area. ² Majority of cases originate as a result of parental balanced reciprocal translocation between chromosome 9 and any other chromosome. ³ Minority of cases originate as de novo, and it is not transmitted through parents. ⁴ A variable degree of intellectual disability is present. ⁵ Characteristic physical features include short stature, microcephaly, dysmorphic facial features, and various skeletal abnormalities. The size of the duplicated region is linked with the degree of clinical severity rather than the plenitude of phenotype. Here, we report an additional case of partial trisomy 9p in an 8-year-old girl, review the clinical features and pathogenesis, and highlight the importance of parental testing in the context of genetic counseling. In addition, we emphasize the importance of different cytogenetic investigations in order to identify the precise nature and location of chromosomal rearrangements.

Case presentation

We describe the case of an 8-year-old girl who was referred to our hospital for clinical evaluation of short stature with initial suspicion of Turner syndrome. She was the first child in the family. Parents and two younger siblings were healthy. She was born on 41st week of gestation with birth weight of 3350 g, birth length 51 cm, and head circumference 32 cm.

Clinical examination of the patient revealed short stature (109 cm, below 3 SD) and dysmorphic features, including bulbous nose tip, ocular hypertelorism, deep-set and almond-shaped eyes, epicanthal folds, low-set ears, high-arched palate, brachydactyly, clinodactyly, and scoliosis (Figure 1(a)–(d)). Furthermore, evaluation demonstrated delayed motor development, delayed speech, mild intellectual disability, and learning difficulties at school.

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Figure 1.

(a) Characteristic dysmorphic facial features, including bulbous nose and deep-seated eyes, (b) low-set ears, (c) brachydactyly, and (d) clinodactyly.

A magnetic resonance imaging (MRI) scan of the brain showed hypotrophy of the corpus callosum. Ultrasound investigations showed no signs of cardiac disease or any other organ malformations.

Bone age was delayed on hand X-ray and corresponded to 6 years. Complete blood count and sedimentation rate, electrolytes, thyroid function tests, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor–binding protein 3 (IGFBP-3) all showed normal results.

In order to exclude Turner syndrome, karyotyping (350 bands) was performed, which showed atypically elongated short arm of chromosome 15–46, XX, add(15)(p?) (Figure 2(a)); however, the resolution of the karyotype did not allow to define the origin of the abnormality. In order to define the exact nature of the abnormal chromosome, chromosomal microarray – CMA (Single Nucleotide Polymorphism array, 750K) was performed, which revealed pathogenic 38,584 kb-large 1 copy gain within chromosomal region 9p24.3p13.1 (Figure 2(b)). It allowed us to conclude that the extra region on chromosome 15 belonged to the short arm of chromosome 9. CMA was also performed in the parents and the targeted copy number variant was not detected in any of them. In order to exclude the balanced translocation in the parents (which is beyond the detection level of CMA), karyotype was performed, which showed normal chromosomal constitution in both of them. Taking together karyotype and CMA test results of the child and the parents, the de novo nature of the translocation of 9p was confirmed. Currently, the patient is under the care of a multidisciplinary team, including a pediatric developmental specialist, endocrinologist, and orthopedic specialist. Her cognitive performance is mildly below the average, and she is involved in a special education program. Patient’s endocrinological evaluation is currently unremarkable; however, her height is still below the third centile. She is undergoing a regular physical therapy and her scoliosis is stable.

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Figure 2.

(a) G-banded karyotype showing atypically elongated short arm of chromosome 15 (arrow) in the proband and (b) result of CytoScan 750K array exhibiting duplication of 9p terminal region (arrow).

Discussion

Chromosomal duplications result from replication errors within one chromatid, through an unequal crossing over between sister chromatids or by translocation between homologous chromosomes. ⁶ The term partial trisomy is sometimes used, especially for larger classical duplications. It can be present as an isolated duplication, uncomplicated by other rearrangements, or in combination with a deletion or other events (isochromosomes, dicentrics, derivatives, recombinants, rings, and markers). The phenotypic changes of patients with segmental duplication are usually less deleterious compared to the deletion of the same region. However, as duplication in a gamete results in chromosomal imbalance, such abberations often results in various phenotypic abnormalities. ⁷ The dosage effect due to a duplication is referred to as triplo-excess, or triplo-sensitivity, in contrast to the haploinsufficiency of the deletion. Duplications can be terminal or interstitial. However, by molecular cytogenetic testing, these regions may not coincide with what is seen visibly by conventional karyotype analysis. In order to clearly define whether a duplication is interstitial or terminal, CMA analysis could be performed to reveal the exact breakpoints and size of the abnormality. ⁸

One of the common autosomal duplications resulting in partial trisomy is dup 9p24.3cen. It was initially described in 1970, ⁹ and since then, more than 200 patients have been reported in the literature.^{10 –13} In fact, it is said to be fourth in frequency after the three major full trisomies. Typically, duplication extends into the 9qh heterochromatic region, 9q11q12, and sometimes as far as q21.11. ¹⁴ A scarcity of dosage-sensitive loci within 9p and an accumulation of repeat sequences within the pericentromeric region comprise the basis of its viability. Exact genes causing particular clinical manifestations are not known yet. Most cases occur in the setting of a rearrangement with another chromosome, although isolated cases are also well documented. ¹³ Despite differences in the size of the duplication, phenotypic manifestations in patients with dup9p24.3 exhibit a remarkable consistency, particularly in craniofacial and digital anomalies. ¹⁰ In recent review of 9p deletions and duplications by Sams et al., ¹³ the authors try to link genotypes with phenotypes by an attempt to understand the complex mechanisms of protein–protein interactions and give insights into the molecular pathogenesis of the disease. In future, the application of novel genomic technologies with deep phenotyping could possibly shed light to the understanding of precise genomic mechanisms underlying complex chromosomal rearrangements.

Clinically as analyzed by Cammarata-Scalisi, ¹ the most common manifestations of 9p duplications include neonatal hypotonia, low birth weight, delayed motor and cognitive development (mostly mild), short stature, delayed bone age and delayed puberty, various skeletal manifestations (including short webbed neck, kyphoscoliosis, lordosis, hip luxation, brachydactyly, clinodactyly, and brachymesophalangy), dysmorphic facial features (down and upward slant of palpebral fissures, epicanthal folds, hypertelorism, strabismus, bulbous nose tip, short philtrum, high palate, down-turned corners of mouth, malformed and low-set ears, and microbrachycephaly), various central nervous system (CNS) malformations on brain MRI (cerebral and cerebellar hypoplasia, ventriculomegaly, and agenesis and hypoplasia of the corpus callosum), and congenital heart defects and sometimes epilepsy. ¹⁵

Clinical manifestations in our patient are consistent with findings reported in the literature. This case highlights the importance of cytogenetic investigations in children with developmental delay and intellectual disability, particularly in combination with short stature. It also demonstrates the importance of CMA analysis in the setting when the karyotype is inconclusive for the detailed characterization of chromosomal abnormalities.

Conclusion

We described an additional case of rare de novo chromosome 9p duplication in an 8-year-old girl with major findings of developmental delay, short stature, and dysmorphic physical features. The sequelae of different cytogenetic investigations, including karyotype and CMA, were critical for the precise diagnosis of chromosomal abnormality. Parental testing is of great importance, especially in the context of terminal deletions and duplication allowing estimation of recurrence risk and genetic counseling.