Keywords 7q21.3-q31.1 - array CGH - developmental delay - facial features - duplication
Introduction
Individuals with duplication of long arm (q) have been uncommonly reported. The isolated,
“pure,” 7q form has been classically classified according to the chromosomal anomaly
involving either the entire arm or the interstitial, proximal, and distal portions
of the segment.[1 ]
[2 ]
[18 ] Novales et al[14 ] distinguished the affected individuals according to the chromosome 7q segment with
these results: those presenting interstitial duplication 7q22 to 7q31 showed facial
features consisting of frontal bossing, long eyelashes, narrow palpebral fissures,
epicanthus, hypertelorism, small nose, long upper lip and ocular impairment in absence
of skeletal anomalies, cleft palate, and early death; those with 7q31 to 7qter showed
developmental delay (DD), facial features as large fontanelle, narrow palpebral fissures,
hypertelorism, small nose, cleft palate, micrognathia, low-set and malformed ears,
moreover, skeletal anomalies and early death were also recorded; duplication 7q32
to 7ter was characterized by DD, facial features presenting with small nose, low-set
ears, in absence of micrognathia and cleft palate, skeletal anomalies, neurologic
symptoms, and early death.
In this article, we reported a 3-year-old male child patient with pure partial duplication
of the long arm of chromosome 7 extending for 14.4 Mb from 7q21.3 to q31.1. Clinical
manifestations observed in the child are reported and compared with the clinical features
found in children with the distal segment involved and then with those children who
showed the interstitial chromosome 7q segment involved with the aim to individuate
possible clinical signs specific for each of the segment affected.
Case Presentation
This 3-year-old male child patient is the third child of healthy, unrelated Italian
parents. The two older siblings, a 5-year-old sister and a 7-year-old brother, are
healthy. The family history is negative for genetic disorders. At the time of gestation,
the mother was 32 years old and the father was 35 years old. The mother denied to
have suffering by infectious disease during her pregnancy and do not have smoked cigarettes
or taken drugs during her pregnancy. Intrauterine ultrasound showed growth restriction
by the 7th month and the mother noted that fetal movements were reduced. The child
was delivered at 39 weeks of gestation by cesarean section due to breech presentation.
His birth weight was 2,350 g (3th percentile), length 48 cm (10th percentile), and
occipitofrontal circumference (OFC) 33 cm (3th percentile). At the second day of life,
the child suffered by respiratory distress and he was admitted to Neonatal Intensive
Care Unit, Department of the Pediatric Clinic, University of Catania, Italy for treatment
and investigations. Cranial ultrasound displayed light hypodensity of the periventricular
white matter. Echocardiogram showed pulmonary valve stenosis with atrial septal defect.
At 10 days from birth, he was discharged in good condition without indication for
a prompt cardiac intervention. During the first month, his clinical picture was mostly
characterized by minor facial features and delayed developmental milestones particularly
as regards hypotonia. At the age of 2.5 years, the child was admitted to the Pediatric
Department of Catania University, Italy, for checkup due to DD and craniofacial anomalies.
At this age, the weight was 12 kg (10th percentile), length 88 cm (10th percentile),
and OFC 47 cm (3th percentile). According to the “Elements of Morphology: Standard
Terminology” (Am J Med Genet 2009, 149A (1): 1–127), he showed craniofacial features consisting of microcephaly,
turricephaly, prominent frontal bossing, arched eyebrow shaved in the medial part,
inner epicanthic folds, down-slanting palpebral fissure, flat nasal bridge, thin nose
with rounded tip and anteverted nostrils, flat filter, thin lips, low implanted ears
with rotated axis, and thin hair.
Muscular masses were hypotonic with poor subcutaneous tissue. He showed ankles valgism,
knees in arthrogryposis, keeled chest, scapular winging, hands joint laxity, and abdominal
rectus diastasis. DD was present, he was able to pronounce a very few words. The walk
was unsteady. Patellar osteotendinous reflexes were hypo-eligible. Systolic murmur
2/6 Levine was appreciable and echocardiogram confirmed the presence of pulmonary
valve stenosis with atrial septal defect. Left cryptorchidism was present at the routine
laboratory analysis electrolytes, plasma and urinary amino acids, thyroid markers,
organic acids, plasma purine, transferrin isoelectric focusing, and total cholesterol
were within normal limits. Electroencephalogram in awake and during sleep was normal.
Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging sequences showed
a regular volume and anatomy of the subtentorial and supratentorial structures and
ventricles. The spine MRI pointed out a cleft in the S5 posterior arch, a distal sacral
lipomatosis from S3 to S5, and a small periapical cyst Tarlov type at the right S2
([Figs. 1 ] and [2 ]).
Fig. 1 Spine magnetic resonance imaging showing S5 posterior arch cleft and distal sacral
lipomatosis.
Fig. 2 Spine magnetic resonance imaging showing S2 periapical cyst.
Genetic Testing
High definition karyotype analysis was performed after culture of lymphocytes for
the child and his parents, according to the International System for Human Cytogenetic
Nomenclature;[11 ] mean resolution was 550 bands; Cytocell painting probe was used for molecular cytogenetic.
Array comparative genomic hybridization (CGH) (human DNA, Promega) analysis using
Cytofure ISCA 8 × 60K v.2 (protein O-GicNac Transferase, OGT) was performed on genetic
DNA extracted from peripheral blood samples from the child and his parents. Software
analysis was Cytofure Analysis Software (genomic assembly University of California,
Santa Cruz, UCSC hg 19). Quality score (Derivative Log Ratio Spread, DLRS) was <0.25.
Analysis parameter: four consecutive probes. Resolution: 50 to 100 Kb. Next-generation
sequencing (NGS) panel for RASopathies was performed.
Results
Analyses showed in the child a 46, XY karyotype with intrachromosomal partial duplication
of the long arm of chromosome 7, extending for 14.4 Mb (7q21.3-q31.1): arr [hg 18]
([Fig. 3A, B ]). The centromeric margin of the duplication is made by the normal oligomer in position
95054968pb and the duplicated oligomer in position 109476740pb. The telomeric margin
is made by the normal oligomer in position 109557905pb and the duplicated oligomer
in 109476740bp ([Fig. 4 ]). RASopathies NGS analysis did not show any alteration. Parents' karyotype and array
CGH were normal.
Fig. 3 (A,B ) Karyotype of the child showing intrachromosomal partial duplication of the long
arm of chromosome 7.
Fig. 4 Imaging modified from OMIM showing genes included in the rearranged region.
Discussion
Our patient showed a complex of congenital anomaly consisting of minor, nonspecific
craniofacial features, microcephaly, mild DD, and heart and skeletal impairment. Genital
organs, hands, and abdomen were also involved. Congenital heart disorder (CHD) consisted
of pulmonary valve stenosis with septal defect; skeletal anomalies showed cleft of
S5 posterior arch, distal sacral lipomatosis from S3 to S5, and right S2 periapical
cyst Tarlov type; knees in arthrogryposis and ankles valgism were also present. In
addition, abdominal rectus muscle diastasis, left cryptorchidism, and hands joint
laxity were noted. Array CGH showed a large genomic duplication of 14.4 Mb on chromosome
7q21.q31.1 harboring several OMIM and RefSeq genes: the rearranged region includes
more than 230 genes ([Fig. 4 ]). According to SFARI gene database, some of those such as ACTL6B , FOXP2 , PONI , KMT2E are involved in synaptic plasticity and autistic signaling mechanisms and other structural
anomalies ([Fig. 5 ]) with causative effect in congenital disorders affecting brain and other organs.
Fig. 5 Imaging modified from SFARI genes showing genes involved in autism spectrum disorder
high confidence.
Chromosome 7q is susceptible to different structural rearrangements. Attempt to highlight
specific clinical signs according to each of the interstitial, proximal, or distal
segment involved has been not clearly defined. Alfonsi et al tried to compare the
clinical features of a case of their observation presenting partial chromosome 7q
duplication involving the region q21.1-q22.3 with six patients extracted from the
literature with similar 7q rearrangement.[1 ] These authors found concomitant presence of intellectual delay and low-set malformed
ears in all the cases including their own; ocular squint and frontal bossing features
in six; and skeletal anomalies in five. Three of the patients showed genital urinary
defects, macrocephaly, and some similar craniofacial features such as hypertelorism,
small upturned nose, microretrognathia, cleft palate, and high arched palate. The
authors draw the conclusion that in individuals with pure chromosome 7q proximal segment
involved, specific diagnostic clinical features were not raised.[1 ]
In this study, we analyzed clinical data of each of the eight cases of 7q pure duplication
interstitial (7q22 to 7q32) segment reported in the literature including the present
case to evaluate clinical similarity or differences ([Table 1 ]). In the interstitial groups, no gender prevalence was noted as three males and
four females were the children affected. DD and minor, nonspecific facial features
were reported in all the cases. In particular, looking at some facial features, frontal
bossing and epicanthus were reported in six out of seven, low-set ears in four, and
microretrognathia in two cases. Hypotonia, growth retardation was found in six and
ocular squint in five out of seven cases. Three children were microcephalic, and heart,
skeletal, and genital anomalies were reported only in the present case but not in
the others. Hirsutism and hip subluxation were reported in two cases and cerebral
malformation and renal dysplasia only in one case.[2 ]
[4 ]
[7 ]
[15 ]
[17 ]
[18 ]
[21 ] Analyzing these results, it appears evident that except for intellectual delay and
minor craniofacial delay, no specific clinical signs have been raised to indicate
a clear diagnosis.
Table 1
Clinical data of eight cases presenting pure 7q distal duplication[1 ]
[3 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ] in comparison with the present case presenting pure 7q interstitial duplication
Distal 7q
Present case
Gender
M/F: 7/1
M
Facial features
8/8
+
Large head
5/8
−
Developmental delay
8/8
+
ASD
1/8
−
Skeletal anomalies
4/8
+
Genitourinary anomalies
2/8
+
CHD
1/8
+
Abbreviations: ASD, autism spectrum disorder; CHD, congenital heart disorder.
We extended our study examining clinical data of pure distal versus pure interstitial
7q duplication comparing the six cases reported in the literature with those observed
in the present child ([Table 2 ]).[3 ]
[6 ]
[10 ]
[17 ]
[20 ]
[22 ] Analyzing these results, it appears evident that minor nonspecific craniofacial
features, intellectual delay, and skeletal impairment with minor frequency were the
most representative clinical signs presented both in the group of children with distal
and in the present child with interstitial chromosome 7q involvement.
Table 2
Clinical data of the six reported cases (8, 11–15) plus the present case with pure
interstitial 7q duplication
Grace et al (1972)
Berger et al (1974)
Serville et al (1975)
Romain et al (1990)
Mégarbané et al (2000)
Weimer et al (2011)
Present case
Total
Chromosome 7
q22-q32
q21-q31
q22-q31
q22-q31.2
q22-q31.3
q21.1-q31.3
q21.3-q31.1
Sex
F
M
M
F
F
F
M
3 M/4 F
Facial features
Frontal bossing
−
+
+
+
+
+
+
6/7
Epicanthus
+
+
+
+
+
+
+
6/7
Microretrognathia
−
−
−
−
+
−
+
2/7
Low-set ears
+
−
+
−
+
−
+
4/7
Development delay
+
+
+
+
+
+
+
7/7
Microcephaly
−
−
−
−
+
+
+
3/7
Hypotonia
−
+
+
+
+
+
+
6/7
Growth retardation
+
−
+
+
+
+
+
6/7
CHD
−
−
−
−
−
−
+
1/7
Genital anomalies
−
−
−
−
−
−
+
1/7
Skeletal anomalies
−
−
−
−
−
−
+
1/7
Ocular anomalies
−
+
+
+
+
+
−
5/7
Other anomalies
−
−
+
+
+
+
+
5/7
Abbreviations: CHD, congenital heart disease; F, female; M, male.
Note: The other anomalies include: hirsutism reported in two cases (14 and 15); hearing
loss and renal dysplasia in one;[8 ] and spine anomalies in the present case.
Aside pure, isolated chromosome 7q duplication, the 7q anomaly may occur in association
with rearrangements involving the same or other chromosomes causing different and
more complex clinical manifestations. Frühmesser et al reported a case of partial
trisomy 7q22q32 with additional inversion of 7q31.2.2q32.3.[15 ] The child showed DD, growth failure, hands anomalies, and CHD presenting with patent
ductus arteriosus and patent foramen ovale.
Craniofacial features consisted of frontal bossing, slightly down-slanting palpebral
fissures, broad nasal root, long philtrum micrognathia, and prominent ears. Paththinige
et al reported on a female child trisomic for 7q22.-qter and minimal loss of genetic
material on chromosome 14.[13 ] Intrauterine growth retardation, DD, and ventriculomegaly were the main signs with
craniofacial features presenting with asymmetric skull, triangular face shape, high
forehead, hypertelorism, flat nasal bridge, micrognathia, and low-set malformed ears.[16 ] The authors agreed with the results of the literature that in this case, no clear
correlation genotype–phenotype was found.
The present child showed a CHD consisting of a stenosis of the pulmonary valve, an
anomaly which is reported as one of the typical signs of Noonan's syndrome. This syndrome
is related to alterations involving the RAS-MAPK pathway[17 ] as it falls into a group of disorders called “RASopathies” which share common dysregulation
of RAS/MAPK pathway. Due to some common clinical signs with the present child including
the cardiac defect, we extended the genetic research with NGS panel for RASopathy
principal genes which in our case gave negative results. In addition, the present
child showed anomalies affecting the skeletal system, in particular, the spine with
S5 posterior arch cleft, sacral lipomatosis, and sacrococcygeal anomalies. The anomalies
(the last one) are part of the Currarino syndrome (CS).
CS known as autosomal dominant sacral agenesis is a well-known disorder characterized
by a classic triad of partial absence of the sacrum with intact first sacral vertebra,
presacral mass, and anorectal anomalies.[18 ] CS may manifest with a variable clinical expression ranging from only caudal anomalies
to complex organ system malformation. The disorder has been related to a deleterious
variants of HLXB9 , a homeobox gene mapped to chromosome 7q36.[8 ] Pavone et al reported a female child with pre- and postnatal growth retardation
and complex malformations with microcephaly, lack of cortical thickening, hypoplastic
inferior vermis in association with signs of CS as partial sacral agenesis and complete
coccygeal agenesis, preintrasacral dermoid, intradural lipoma, ectopic anus, and tethered
cord.[19 ]
[20 ]
[21 ]
[22 ] The child showed a de novo duplication of 7q34-q35 and an 8.8-Mb deletion on 7q36.
This sequence includes HLXB9 (CS) gene which in the case report of Pavone et al was not found.[14 ] Clinical relationship between the spine anomalies reported in the present child
and those reported in CS remain to be established.
Conclusion
In conclusion, clinical signs and body organs presenting in individuals with involvement
of the different proximal, interstitial, and distal pure segments of q7 duplication
are nonspecific and not diagnostically indicative. The same results were reached for
what it regards the single case with involvement the interstitial segment involved
as with the exception of no distinctive facial features and mild DD nonspecific, indicative
diagnostic signs were reported.
