Maternal uniparental disomy 14 and mosaic trisomy 14 in a Chinese boy with moderate to severe intellectual disability

Background Both maternal uniparental disomy 14 (UPD(14)mat) and mosaic trisomy 14 are rare events in live individuals. A combination of the two events in one individual is rarely encountered. Only six live-born cases have so far been reported. Case presentation Here we reported a case of concomitant UPD(14)mat and mosaic trisomy 14 in a 10-year-old Chinese patient. Most clinical features of our patient were consistent with those previous reported for UPD(14)mat cases, which include prenatal and postnatal growth retardation, neonatal hypotonia, feeding difficulty, intellectual disability, truncal obesity, small hands and feet, short stature, and mild facial dysmorphism, but our patient showed more severe intellectual disability and no sign of precocious puberty. SNP array analysis revealed a mixture of chromosome 14 maternal isodisomy with heterodisomy and a low level trisomy mosaicism of whole chromsome 14 in blood and hyperpigmented skin samples, whereas only UPD(14)mat was detected in normal skin sample. Cytogenetic analysis identified one trisomy 14 cell in 100 metaphase of peripheral blood lymphocytes (47,XX, +14[1]/46,XX[99]). Conclusions To our knowledge, this is the first case of a patient with UPD(14)mat and mosaic trisomy 14 reported in a Chinese patient. The definitive genetic diagnosis is beneficial for genetic counseling and clinical management of our patient, and for improving our understanding of the genotype-phenotype correlations of concomitant UPD(14)mat and mosaic trisomy 14. Electronic supplementary material The online version of this article (doi:10.1186/s13039-016-0274-4) contains supplementary material, which is available to authorized users.

Trisomy 14 mosaicism is a rare chromosomal abnormality with distinct and recognizable clinical features, including growth and psychomotor retardation, short neck, congenital heart defect, genitourinary abnormalities, body asymmetry, abnormal skin pigmentation and craniofacial dysmorphism [14]. So far, 42 live-born cases have been reported [15,16].
The first case of UPD (14)mat with mosaic trisomy 14 confirmed at peripheral blood lymphocytes level was described by Antonarakis et al. [17]. So far only six live-born patients have been previously reported [4,[17][18][19][20][21], four out of the six patients involved no Robertsonian translocations or ESACs. Here we reported a seventh live case of UPD (14)mat and mosaicism for trisomy 14 (the fifth case without involvement of Robertsonian translocations or ESACs).

Case presentation
Patient A 10-year-old Chinese boy was born to a healthy gravida 2, para 2 mother with negative family history for genetic diseases. At the time of his birth, his mother and father were 35 and 36 years old respectively. Ultrasonic examination showed intrauterine growth retardation and polyhydramnios. He was delivered by Caesarean section at full term with a birth weight of 2350 g (3rd centile). The birth height was unknown. He had a history of developmental delay and neonatal hypotonia. He had delayed milestones, feeding difficulty and week sucking and crying during the first several months of life. At the age of five, his complete blood count and thyroid-stimulating hormone (TSH) were normal, but the serum growth hormone (GH) level was very low (0.97 ng/ml). Growth hormone provocative test showed a peak value of 2.66 ng/ml and the patient was diagnosed with growth hormone deficiency (GHD). He began to get fat with a growth rate of 2-3 cm per year when he was 6 years old and his bone age was delayed (corresponded to the age of 2 years). He is now presented with intellectual disability, language delay, learning difficulty, attention deficit and minimal communication with his peers. Physical examination at age of 9 years and 9 months showed a height of 118.3 cm (−6.0SD), a weight of 27 kg (−1.5SD) (BMI = 19.3 kg2/m), and OFC of 52 cm (50-75th percentile). He had small hands with a length of 13.5 cm and small feet with a length of 18.5 cm (The average is 20.5 cm for Chinese boys at 7-10 years of age). His physical features include short stature, truncal obesity, short neck, thoracic-lumbar scoliosis, lordosis and kyphosis, small hands and feet, fifth finger clinodactyly, buffalo hump, barrel chest, body asymmetry, cryptorchidism on the right side and abnormal skin pigmentation (Fig. 1). His craniofacial features included ocular hypertelorism, narrow palpebral fissures, high arched palate, and depressed nasal bridge. The right and left testes were 1.7*0.8*1.0 cm and 1.7*0.9*1.1 cm in size respectively. The size of penis was 4.0*1.5 cm without pubes. No sign of precocious puberty was noticed. ECG examination showed sinus cardiac arrhythmia and brain MRI examination was normal. A recent assessment using Chinese Wechsler intelligence scale for children (C-WISC) showed a verbal scale IQ of 35 (severe), a performance scale IQ of 55 (mild), and a full scale IQ of 38 (severe). Raven's Standard Progressive Matrices (RSPM) was also used to measure his intelligence. The intelligence percentile rank was 6 %. Based on the intelligence test results above, the patient was diagnosed with moderate to severe intellectual disability. Meanwhile his motor development was close to normal level. The boy started growth hormone (GH) therapy at the age of 9 years and 9 months. He grew 4.9 cm (from 118.3 to 123.2 cm (−5.0SD)) during the first five months. He also gained 5 kg of weight (from 27 to 32 kg (−0.5SD)).

Cytogenetic and molecular analyses
Peripheral blood lymphocytes, hyperpigmented and normal skin samples were collected from the patient and genomic DNA was extracted using Lab-Aid DNA kit (Zeesan Biotech Co., Ltd, China). G-banding was performed on metaphase chromosomes of cultured peripheral blood lymphocytes of the family trio. FISH was directly conducted on interphases chromosomes 14 of peripheral blood lymphocytes with probe specific for the region 14q11.2 (Agilent, USA, Spectrum red) on the patient. Genomic profiling were performed on blood, hyperpigmented and normal skin samples of the patient and his parents' blood samples using Illumina Human CytoSNP 12 BeadChip array (Illumina, San Diego, CA). The SNP array data was analyzed with GenomeStudio and KaryoStudio software. All operative procedures fully followed the manufacturer's instructions.

Discussion
This is the seventh liveborn reported with a combination of UPD (14)mat and mosaic trisomy 14 and the first case in a Chinese patient. The presence of mosaic trisomy suggest that UPD was formed by trisomy rescue. The finding of tissue restricted trisomy mosaic pattern further suggested somewhat delayed post-zygotic trisomy rescue. In addition, the UPD(14)mat presented as a mixture of isodisomy and heterodisomy in our patient, we speculated that at least two crossover events had happened between the two non-sister chromatids of homologous chromosomes at the maternal meiosis I and a disomic gamete arose from nondisjunction in maternal meiosis II [12].
Most of the clinical features of our patient were consistent with those previous reported for UPD (14)mat cases, which included intrauterine growth retardation, neonatal hypotonia, short stature, truncal obesity, small hands and feet, intellectual disability, and mild facial dysmorphism, but our patient showed more severe intellectual disability. In previous reports, most cases had normal intelligence and no more than one-third of cases showed mild to moderate intellectual disability, whereas our patients presented with moderate to severe intellectual disability [3]. In addition, our patient also presented with some clinical features of trisomy 14 mosaicism which include polyhydramnios, abnormal skin pigmentation, short neck and cryptorchidism. We compared the clinical features of five patients with UPD (14)mat and mosaic trisomy of whole chromsome 14 in Table 1 (Column 4-8). We limited the  comparison among live cases and excluded two cases with the involvement of Robertsonian translocation [17,18]. All cases presented hypotonia. IUGR, short stature and truncal obesity were consistent features. It is unclear if these features were present in the patient reported by Pecile et al. [21]. Moderate intellectual disability was described in two patients reported by Balbeur et al. and Cox et al. respectively [4,20]. The mental status was not mentioned for the other two previously reported patients [19,21]. Based on the C-WISC and RSPM evaluation, our patient was determined to have moderate to severe intellectual disability. No consistent or recognizable facial feature was identified among the five patients. In addition, we compared the clinical features of the five patients with the summaried features of patients with only UPD (14) [20]. Thus it is not known if trisomy 14 mosaicism directly contributed to the abnormal skin pigmentation phenotype.
UPD (14)mat patients demonstrated overlapping features with Prader-Willi syndrome (PWS) including hypotonia, neonatal feeding difficulty and obesity. UPD(14)mat should be considered as a differential for patients with suspected PWS. Indeed, Mitter et al. detected four UPD(14)mat from 33 patients who were suspected to have PWS [9]. Similarly, Hosoki et al. identified four UPD(14)mat patients from a 78 patient cohort with PWS-like phenotype without known molecular defects for PWS [10]. However, Cox et al. did not find any UPD (14)mat in 35 patients suspected with PWS [4]. Further studies could help to identify other distinguishing features such as facial characteristics and precocious puberty for differential diagnosis.
Four UPD (14)mat patients had been previously described with GH treatment, and all patients showed beneficial effects. But only one patient was known to have growth hormone deficiency [9], and other three cases were treated because of short stature without data regarding the GH level [19,22]. The height SDS (HSDS) of patient with growth hormone deficiency increased from −2.5SD at age of 6 to −1.5SD at age of 12 [9]. Two patients presented a considerable increase in height (from −2.3SD at age of 6.9 to −1.2SD at age of 8.9, from −1.2SD at age of 9.3 to −0.6SD at age of 11.4, respectively) and IGF-1 level (from +0.1SD to +1.3SD, from −1.4SD to +0.9SD, respectively) [19]. The remaining patient received growth hormone therapy at age of 4 because of short stature (−3.9SD at 3 years 11 months) and obtained effective result without specific data about height [22]. The treatment effect on body composition was less consistent among them. In one patient, her weight decreased from +1.2SD to −0.7SD and the body composition was improved (fat percentage from 51.5 % to 45.4 %), and in other patient, his weight and body composition remained stable [19]. The GH level was rarely measured among the UPD(14)mat patients, our patient was the second case to undergo growth hormone provocative test. Due to the complete growth hormone deficiency, our patient started the recombinant human growth hormone replacement treatment at the age of 9 years and 9 months. After five months of treatment, his height increased from −6.0SD to −5.0SD. Contrary to previous reports, his weight increased from −1.5SD to −0.5SD which may be caused by other unknown endocrine problems or overeating behavior. The clinical presentation described for this patient and his response to GH treatment is useful for future patient counseling and care.

Conclusions
In summary, we described the first Chinese patient with UPD(14)mat and mosaic trisomy 14. Our patient presented with prenatal and postnatal growth retardation, neonatal hypotonia, feeding difficulty, intellectual disability, short stature, truncal obesity, small hands and feet, and mild facial dysmorphism, mostly consistent with features known to be associated with UPD(14)mat. The patient had complete GH deficiency and benefited for growth hormone replacement treatment. The definitive genetic diagnosis is beneficial for genetic counseling and clinical management of our patient, and for improving our understanding of the genotype-phenotype correlations of concomitant UPD (14)mat and mosaic trisomy 14.