Pure interstitial 7q21.3-q 31.1 duplication: rare segmental genomic aneuploidy: case report and review of cases involving distal and similar segments

Case presentation

This 3-year-old male patient is a healthy, third child of unrelated Italian parents. The two siblings (a 5-year-old sister and a 7-year-old brother) are healthy and have no family history of genetic disorders . At the time of his pregnancy, his mother was 32 years old and his father 35 years old. Her mother denies having any infections during pregnancy, and she has never smoked or taken any medication during pregnancy. Intrauterine ultrasound showed developmental stricture by 7 months, and the mother noted decreased fetal movements. The child was delivered by caesarean section at 39 weeks of gestation due to breech position. Birth weight was 2,350 g (3rd percentile), length 48 cm (10th percentile), and occipitofrontal circumference (OFC) 33 cm (3rd percentile). On the second day of life, the child suffered from respiratory distress and was admitted to the neonatal intensive care unit of the Pediatric Clinic of the University of Catania, Italy, for treatment and examination.
Head ultrasound showed mild hypodensity of the periventricular white matter. Echocardiography showed pulmonary valve stenosis with an atrial septal defect. On day 10 of life, the patient was discharged from the hospital in good condition without indication for immediate cardiac intervention. During the first month, the patient’s clinical picture was mainly characterized by minor facial features and delayed developmental milestones, especially regarding hypotonia. At 2.5 years of age, the child was admitted to the Department of Pediatrics of the University of Catania, Italy, for evaluation for developmental delay and craniofacial anomalies. At this age, weight was 12 kg (10th percentile), length 88 cm (10th percentile), and OFC 47 cm (3rd percentile). According to “Morphological elements: standard terminology: Am J Med Genet 2009, 149A (1): 1-127”: microcephaly, tarry encephalopathy, prominent frontal protuberance, arched eyebrows with shaved medial area. , from the medial superior corner folds, downward facing palpebral fissures, flat nasal bridge, thin, flat filter of the nose with a rounded tip and anteverted nostrils, thin lips, low recessed ears with axes of rotation, and thin hairs. It showed craniofacial features.
The sarcoma was hypotonic and the subcutaneous tissue was poor. The patient presented with ankle valve stenosis, knee in joint contracture, keel chest, scapular wing, wrist laxity, and rectus abdominis diastasis. He was developmentally delayed and was able to say very heavy words. His gait was unsteady. Osteonecrosis of the patella and loss of reflexes are ineligible. Systolic mouse 2/6 Levine was marked, and echocardiography confirmed the presence of pulmonary valve stenosis with an atrial septal defect. Routine laboratory analysis of electrolytes, plasma and urinary amino acids, thyroid markers, organic acids, plasma purines, and transferrin isoelectric focusing revealed left cryptorchidism, and total cholesterol was within normal limits. EEG during wakefulness and sleep were normal. Brain magnetic resonance imaging (MRI) using a diffusion-weighted imaging sequence showed regular volumes and anatomy of infratentorial and supratentorial structures and ventricles. Spinal MRI revealed a cleft in the posterior arch of S5, lipomatosis of the distal sacrum from S3 to S5, and a small Tarlov type periapical cyst in the right S2 ( see Figures 1 and 2 ).

Figure 1 Spinal magnetic resonance image showing S5 posterior arch cleft and lipomatosis of the distal sacrum.

Figure 2 Spin magnetic resonance imaging showing an S2 periapical cyst.

Figure 3 (A,B) Caryotype of a child showing intrachromosomal partial duplication on the long arm of chromosome 7

Figure 4 Imaging modified from OMIM showing genes included in the reconstructed region

Consideration

The child exhibited a complex of congenital anomalies consisting of mild nonspecific craniofacial features, microcephaly, mild developmental delay, and cardiac and skeletal defects. The genitals, hands, and abdomen were also affected. Congenital heart disease consisted of pulmonic valve stenosis with septal defect, skeletal abnormalities showed S5 posterior arch fissure, S3-S5 distal sacral lipomatosis, and right S2 periapical cyst Tarlov type; joint contractures. and knee in ankle valve stenosis were also present. Additionally, rectus abdominis diastasis, left cryptorchidism, and wrist laxity were observed. Array CGH revealed a large genomic duplication of 14.4 Mb on chromosome 7q21.q31.1 with several OMIM and RefSeq genes : the rearranged region contains more than 230 genes ( Figure 4 ). According to the SFARI gene database, some such as ACTL6B, FOXP2, PONI, KMT2E are involved in synaptic plasticity and autistic signaling mechanisms as well as other structures responsible for congenital diseases affecting the brain and other organs. It is involved in physical abnormalities ( Fig. 5 ).

Figure 5. Image of modified SFARI gene showing genes involved in autism spectrum disorder.

Chromosome 7q is susceptible to different structural rearrangements. Attempts to highlight specific clinical signs depending on the involved stromal, proximal, or distal segments have not been clearly defined. Alfonsi et al. compared the clinical characteristics of an observed case presenting with a partial chromosome 7q duplication involving the q21.1-q22.3 region with six patients from the literature with similar 7q rearrangements. I tried. These authors found intellectual retardation and the presence of low-set malformed ears in all cases, including their own, strabismus and frontal features in 6 cases, and skeletal abnormalities in 5 cases. Three of the patients exhibited several similar craniofacial features such as genital defects, macrocephaly, and high eyelids, small upturned nose, retrognathia, cleft palate, and high arched palate. . ¹ The authors concluded that patients with pure chromosome 7q proximal fragments did not develop specific diagnostic clinical features. ¹ In this study, we analyzed the clinical data of each of the 8 cases of the 7q duplication interstitial (7q22-7q32) segment reported in the literature, including this case, and evaluated clinical similarities or differences ( Table 1 ) . . In the interstitial group, 3 males and 4 females were affected, with no gender-specific prevalence. Developmental delay and mild nonspecific facies were reported in all cases. In particular, looking at some facial features, frontal prominence and epicanus were reported in 6 out of 7 cases, low-set ears in 4 cases, and retrognathia in 2 cases. Hypotension and growth retardation were observed in 6 of 7 cases, and intraocular strabismus was observed in 5 cases. Three children had microcephaly, and abnormal cardiac, skeletal, and genital sweating was reported in this case but not in the other children. Hirushutism and hip subluxation were reported in one case, and brain malformation and renal dysplasia were only in one case. ^{2 , 4 , 7 , 15 , 17 , 18 , 21} Analysis of these results reveals that, with the exception of intellectual retardation and mild craniofacial delay, no specific clinical signs indicating a clear diagnosis were raised. be.

We reviewed clinical data for pure interstitial 7q duplications and pure interstitial 7q duplications , comparing 6 cases reported in the literature with 6 cases currently observed in children ( Table 2 ). ^{3 , 6 , 10 , 17 , 20 , 22} Analysis of these results suggests that few nonspecific craniofacial features, intellectual delay, and a small frequency of skeletal disorders are associated with distal and interstitial chromosome 7q. It seems clear that infiltration is the most typical clinical sign in any of the current groups of children.

F Female. M Male.
Note: Other abnormalities include hirsutism reported in 2 cases (14, 15), hearing loss and renal dysplasia reported in 1 case 8, and spinal abnormalities reported in the present case. .

Except for pure isolated 7q chromosome duplications , 7q aberrations can occur in association with rearrangements involving the same chromosome or other chromosomes, leading to different and more complex clinical symptoms. Fruhmesser et al. reported a case of partial trisomy of 7q22q32 with an additional inversion of 7q31.2.2q32.3 . ^Fifteen children presented with congenital heart disease presenting with developmental delay, failure to thrive, hand abnormalities, patent ductus arteriosus and patent foramen ovale.
Craniofacial features consisted of a frontal protuberance, slightly downward-pointing palpebral fissures, wide nasal root, long affine micrognathia, and prominent ears. Pathtinige et al. reported minimal loss of genetic material on chromosome 14 in girls with trisomy 7q22.-qter. ¹³ Intrauterine growth retardation, developmental retardation, and ventriculomegaly are associated with craniofacial syndromes that present with asymmetrical cranium, triangular facial shape, high cephalopathy, hypercephaly, frontal lobe, flat nasal bridge, micrognathia, and low-set malformed ears. It was the main symptom with characteristics. ¹⁶ The authors agreed with the results in the literature that no clear genotype-phenotype correlation was observed in this case.
The patient presented with a congenital heart defect consisting of pulmonary valve stenosis, an abnormality reported as one of the classic manifestations of Noonan syndrome . This syndrome is associated with alterations involving the RAS/MAPK pathway, as it belongs to a group of diseases called RASopathies that share a common dysregulation of the RAS/MAPK pathway ^. Due to the current common clinical manifestations in children, including cardiac defects, we expanded our genetic studies using an NGS panel for RASopathy key genes, with negative results in this case. Furthermore, the patient exhibited abnormalities affecting the skeletal system, particularly the spine with S5 posterior arch fissure, sacrococcygeal lipomatosis, and sacrococcygeal malformation. The abnormality (the last one) is part of Currarino syndrome (CS).
CS, known as autosomal dominant sacral agenesis, is a classic triad characterized by partial loss of the sacrum, with damage to the first sacral vertebra, presacral mass, and anorectal anomaly. ¹⁸ CS can have a variety of clinical manifestations, ranging from malformations of the tail alone to complex organ system malformations. The disease is associated with deleterious variants in HLXB9, a homeobox gene mapped to chromosome ^7q368 . Pavone et al. reported that a female infant presenting with prenatal and postnatal growth retardation and complex malformations with microcephaly, lack of cortical thickening, lower vermis hypoplasia, signs of CS, sacral segmental agenesis and complete coccygeal agenesis. reported that it was observed as intrasacral dermoid, intradural lipoma, ectopic anus, and tethered cord. Children ^19-22 showed a de novo duplication of 7q34-q35 and an 8.8-Mb deletion of 7q36. This sequence includes the HLXB9 (CS) gene, and no case report of Pavone et al. was found. ¹⁴ A clinical relationship between the spinal malformations reported in this child and those reported in CS has not yet been established.