The concurrence of a short arm isochromosome and a whole long-arm translocation involving a single chromosome has been described in nine children with duplication of 4p (one patient), 5p (two patients), 9p (four patients), or 12p (two patients) (Marques-de-Faria and Hackel, 1989).
We report here the first instance of concurrent de-novo isochromosome 10, i(10p) and i(10q), in a preterm 33-week male baby delivered by Cesarean section. Birth weight was 1.79 kg, and Apgar score was 8 and 9 at 1 and 5 min, respectively. His father is a 55-year-old Egyptian, and his mother is a 48-year-old Filipino lady. The mother had a long history of uncontrolled diabetes using an oral hypoglycemic. The mother was on insulin therapy during pregnancy. She was a heavy smoker and worked in a hair salon using hair dyes bare handed. Regarding her obstetric history, there was one still birth male baby due to difficult delivery, followed by three times first-trimester miscarriages, then two phenotypically normal children (Fig. 1). She suffered from pregnancy induced hypertension. Antenatal ultrasound revealed polyhydraminos with very short limbs and single umbilical artery. Upon delivery, the baby was admitted to the NICU. The occipitofrontal circumference and length was on the 50th centile. He had dysmorphic features including a hairy forehead, low-set posteriorly rotated ears, bifid antitragus bilaterally, severe micrognathia, cleft palate, and short webbed neck. Both hands showed three rays of fingers with small proximally placed thumbs, partial syndactyly of second/third fingers and third/fourth fingers, and bilateral simian creases. In addition, he had very short lower limbs. The external genitalia showed hypoplastic dark scrotum with normal-sized phallus, left testis in the inguinal canal, and right one not palpable, with anteriorly displaced anus (Fig. 2).
Babygram (Fig. 3) showed bilateral nonvisualized tibiae and fibulae, bilateral hypoplastic femurs, narrow thorax, hypoplastic scapulae, and normal upper limbs. Ultrasound of both head and abdomen was normal. Cardiac echo screening was normal except for mild tricuspid regurgitation. MRI brain showed prominent extra axial spaces for follow-up. TORCH screening test was negative. Liver and kidney functions were normal.
Cytogenetic and FISH studies
Fluorescence in-situ hybridization (FISH) analysis was performed at first to rule out trisomy 13, 18, and deletion in chromosome 1q21.1 using locus-specific probes for chromosome 13q14 (RB1), chromosome 18 [locus-specific identifier (LSI) SS18 (18q11.2)], and LSI 1q21.1 (for TAR syndrome on chromosome 1) with control probe 1p36, and all showed normal results indicating absence of deletions or duplications. FISH analysis was performed according to Pinkel et al. (1986). It was applied on metaphase spreads and interphase nuclei on 48 and 72 h short-term cultures. GTG banding technique was performed for the patients and both parents according to Verma and Babu (1995). It showed absence of the two normal chromosome 10 and was substituted by isochromosome 10p [i(10p)] and isochromosome 10q [i(10q)] in all screened metaphases of the patient. Parental karyotypes were normal. These results were confirmed by FISH tests using arm painting probes for chromosome 10p and chromosome 10q, LSI 10p14 and 10q23, and telomere (Tel) 10p/10q (Fig. 4a and b).
A blood sample was sent to the FISH laboratory from Farwanyia Hospital NICU as a case of multiple congenital anomalies in preterm baby 33 weeks with broad hairy forehead, low-set posteriorly rotated ears, micrognathia, short webbed neck, and very short limbs to rule out chromosomal trisomy 13 and 18 or TAR syndrome with microdeletion in chromosome 1q21.1.
FISH analysis was performed at first to rule out trisomy 13, 18, and deletion in chromosome 1q21.1, which showed negative results in the presence of two copies of chromosomes 13, 18, and LSI 1q21.1. Conventional cytogenetics analysis showed absence of the two normal chromosome 10 and was substituted by isochromosome 10p [i(10p)] and isochromosome 10q [i(10q)] in all screened metaphases.
The proband showed dysmorphic facial features in the form of hairy forehead, low-set posteriorly rotated ears, bifid antitragus bilaterally, severe micrognathia, cleft palate, and short webbed neck. Both hands showed three rays of fingers with small proximally placed thumbs, partial syndactyly of second/third fingers and third/fourth fingers, bilateral simian creases, and very short lower limbs. The external genitalia showed hypoplastic dark scrotum with normal-sized phallus; left testis was felt along the inguinal canal, whereas the right one was not palpable, with anteriorly displaced anus. There was no history of consanguinity or of a similar condition in the family.
On reviewing the current literature, three hypotheses were postulated to describe this rearrangement:
- A postzygotic event seems less probable because mosaicism with a normal cell line has not been found (Bernasconi et al., 1996).
- At zygotic level, a balanced transverse chromosomal breakage and reunion between short arms and both long arms of homologous chromosome 10 has occurred (Bernasconi et al., 1996).
- A third hypothesis suggests that the isochromosomes are derived from a single parental chromosome 10, and the most likely mechanism of formation of the rearranged chromosomes in that case is the following: the zygote contained one maternal chromosome 10 and one or no paternal chromosome 10. Subsequently, misdivision at the centromere occurred, leading to two isochromosomes, both with single chromatid. At the next mitotic division, both went into the same daughter cell. In the following cell cycle, normal replication took place. The paternal chromosome 10, if still present at that stage, would have been lost at that point or soon after.
Bernasconi et al. (1996) described a 36-year-old normal healthy woman who was karyotyped because her five pregnancies had terminated in spontaneous abortions during the first 3 months. Cytogenetic investigation disclosed a female karyotype with isochromosomes of 2p and 2q replacing the two normal chromosome 2. Her husband and both of her parents had normal karyotypes. Molecular studies revealed isochromosomes derived from a single maternal chromosome 2, and the most likely mechanism of formation of the rearranged chromosomes in that case is the following: the zygote contained one maternal chromosome 2 and one or no paternal chromosome 2. Subsequently, misdivision at the centromere occurred, leading to two isochromosomes, both with single chromatid. At the next mitotic division, both went into the same daughter cell. In the following cell cycle, normal replication took place. The paternal chromosome 2, if still present at that stage, would have been lost at that point or soon after. We suggest that this mechanism may have occurred in our patient. However, molecular marker studies were needed to detect parental origin of isochromosome 10 in our case, which cannot be afforded in our case, to support either second or third hypothesis. Some existing environmental factors could contribute to defective oogenesis.
The proband’s mother has multiple risk factors in this pregnancy. First, she was 48 years of age at the time of conception. It is well-established that advancing maternal age is associated with subfertility, chromosomal abnormalities, and multiple gestation.
In patients aged 40 years and older, the higher incidence of antepartum complications such as miscarriage, gestational diabetes, placenta previa, and placental abruption has been documented in the literature (Bianco et al., 1996; Gilbert et al., 1999). The increased incidence of miscarriage is thought to be secondary to the increased risk for chromosomal abnormalities in these pregnancies.
Increased risks for fetal/neonatal congenital anomalies, preterm delivery, and low birth weight were statistically associated with age 40 years and older (Cleary-Goldman et al., 2005). This may be one factor that can describe this rare chromosomal rearrangement.
The second factor is long-standing maternal diabetes, which was poorly controlled. Diabetic embryopathy is characterized by congenital anomalies or fetal/neonatal complications in an infant that are linked to diabetes in the mother, such as renal malformations, especially unilateral or bilateral kidney agenesis. In our proband, the abdominal ultrasound was normal, but radiography skeletal survey of the proband showed bilateral congenital absence of tibiae and fibulae, normal spine, bilateral hypoplastic femurs, and narrow thorax with hypoplastic scapulae, which does not fit with caudal regression description. In addition, septal cardiac anomalies and transposition of great vessels are common in diabetic embryopathy (McLeod and Ray, 2002), whereas the proband’s cardiac echo screening showed mild tricuspid regurgitation, which may be caused by other etiological factors.
The third environmental factor is heavy smoking by the mother. The association of cigarette smoking by pregnant women with low birth weight and preterm delivery of their infants is well recognized (Khoury et al., 1989; Lieff et al., 1999), and this was the case with our proband, preterm delivery 33 weeks; his birth weight was on 10th centile. Although maternal smoking during pregnancy is associated with low birth weight regardless of maternal genotype, greater reductions in birth weight have been found among infants whose mothers smoked and had certain variants of the CYP1A1 gene (Lieff et al., 1999). These variants influence the activity of enzymes involved in the metabolism of some of the chemicals found in cigarette smoke (Lieff et al., 1999; Romitti et al., 1999). Children of women who smoke during pregnancy have also been found to have orofacial clefts, limb reduction defects, congenital foot deformities, urinary tract abnormalities, craniosynostosis, and other congenital anomalies 1.5–2 times more frequently than expected in some studies (Woods and Raju, 2001; Little, 2003; Hackshaw et al., 2011). In addition, there is increased risk for gastrointestinal defects, gastroschisis, anal atresia, hernia, and undescended testes, and reduced risk for hypospadias and skin defects was added by Hackshaw et al. (2011). The cleft palate and bone reduction defects present in our patient may be caused by heavy smoking.
The fourth environmental factor is the mother is working in hair salon for more than 20 years and manipulating with hair dyes bare handed. Hairdressers more often gave birth to infants that were small compared with women from the general population. A slightly higher fraction of infants born to hairdressers had a major malformation. Frequent permanent waving and spraying tended to be associated with increased risk of having a growth-retarded infant, and no increased risk was found for individual exposure (Rylander et al., 2002). We suggest that the frequent exposure of the mother may contribute to this chromosomal abnormality and the abnormal phenotype: cleft palate, limb reduction defect, and both hands showed three rays of fingers with small proximally placed thumbs, partial syndactyly of second/third fingers and third/fourth fingers, and bilateral simian creases.
This study presented a case with apparently balanced transverse chromosomal break and reunion, and multiple congenital anomalies can be caused by any of the above-discussed environmental causes, either individually or all together share in this phenotype with this rare chromosomal rearrangement.
Conflicts of interest
There are no conflicts of interest.
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