Clinical comparison between terminal and interstitial 4q deletion in two unrelated children

doi:10.21203/rs.3.rs-2073624/v1

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Clinical comparison between terminal and interstitial 4q deletion in two unrelated children

https://doi.org/10.21203/rs.3.rs-2073624/v1

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Background. The term “4q deletion syndrome” is defined to include two different regions: an interstitial sequence deleted from the centromere to 4q31 and a terminal deletion from 4q31 to 4qter.

Objective. To compare clinical similarities and differences between two unrelated children of the same age observed during the same time period by the same Center, one presenting with a 4q interstitial deletion, the other with a terminal 4q deletion. The clinical manifestations were compared.

Cases Presentation. Clinical manifestations observed in two children from the infancy to the age of 7 years included: craniofacial features, pre- and postnatal growth failure, and speech and developmental delay. Case 1 showed a terminal 4q deletion of about 329.6 Kb extending from 164.703.186 to 165.032.803 nt, Case 2 displayed an interstitial 4q deletion 600.3 Kb long spanning from 71.655.407 to 78.016.622 nt.

Results. Growth retardation, craniofacial features, mild developmental delay and notable speech delay. were reported in both the probands. Precocious crowded dentition was observed in Case 1 and an accessory spleen in Case 2.

Conclusion. Patients with 4q deletion syndrome although sharing main features, exhibited varying clinical manifestations depending on the area and location of the deletion. Similarity and diversity reported for the probands are analyzed. An extensive review of the 4q deletion syndrome is reported.

chromosome 4q deletion

craniofacial malformations

developmental delay

terminal 4q deletion

interstitial 4q deletion

A 4q deletion may involve interstitial and/or terminal regions of chromosome 4 with extensive and generally severe clinical manifestations. Ockey et al. [1] first described the clinical features of a deletion involving the terminal segment of the long arm of the chromosome observed in a 3 and half month-old child with a series of congenital malformations and limb abnormalities consisting of one bone in the left forearm, limitation of the extension of the left elbow, only one finger on the left limb, and bilaterally overriding distal toes. Subsequent observations have better delineated the clinical phenotype of this syndrome. The common phenotypic abnormalities reported in cases of both 4q terminal or interstitial 4q deletions are extensive and involve various organs and body areas.

Due to overlapping features between the interstitial and the terminal 4q deletion, the term ‘4q deletion syndrome’ [2] has been applied and defines a clinical disorder which involve two different regions: an interstitial deletion from the centromere to 4q31 and a terminal deletion from 4q31 to 4qter. The main features of the syndrome manifest with a phenotypic variability that includes developmental delay (DD), speech impairment, congenital heart defects and digital anomalies [1–10]. The reported incidence is estimated at 1 in 100,000 individuals [6]. To express the clinical variability of 4q deletion syndrome Strehle et al. [8] report three children affected by 4q deletion syndrome. They report the variations with which this disorder may manifest in clinical presentation, diagnosis and prognosis including a female fetus diagnosed with del(4)(q33) following chorionic villus sampling at 14 weeks and pregnancy terminated at 18 weeks; a 5-month-old boy with del(4)(q31.3) plus chromosome 6 duplication with complex congenital heart disease who died from cardiac failure and a 2-year-old girl with interstitial del(4)(q22.1q23) with no major malformations, mild dysmorphic features, and only mild developmental delay.

Here, two unrelated children of the same age affected followed simultaneously by the same Institution since infancy are reported. Case 1 exhibited a terminal and Case 2 an interstitial 4q deletion. The aim is to describe similarities and differences by comparison of their clinical features. An extensive description of the clinical manifestations of the 4q deletions is given.

Case 1 (Terminal 4q deleted region)

A 5-year-old male was the first child of healthy unrelated parents [10]. Family history, pregnancy, birth and perinatal period were uneventful. The child has been followed from infancy to its current age due to growth delay, minor craniofacial features and generalized hypotonia. He was born at the 37th week of gestation by vaginal delivery with birth weight 2,800 g, height 46 cm, occipitofrontal circumference (OFC) of 33 cm (all between the 3rd and 10th percentile). His clinical course was characterized by pre-postnatal failure to thrive, minor craniofacial anomalies, crowded and precocious primary dentition, mild developmental stage delay, speech impairment and behavioral disorder with outburst of anger and aggressivity. Encopresis, diurnal and nocturnal enuresis were observed. Minor craniofacial dysmorphism consisted of forehead very high and rounded, congenital symmetrical plagiocephaly, asymmetric face, palpebral fissure small, short nose with large nasal bridge and round tip, microretrognathia, low-set ears, epicanthus and micro-retrognathia. The thumbs were bilaterally adducted but mobile with digital hyperlaxity. Routine laboratory analysis, EEG in awake state and during sleep, ECG and echo and brain MRI were normal. He is receiving speech-language therapy. At the last examination, age of 7 years, his weight was 20 kg, height 115 cm, and OFC 51 cm (all within the 25th percentile). Clinical features of the child are unmodified. There is a mild intellectual disability (I.Q. 55 at WISCH III) with good socialization and behavioral disturbances with frequent outbursts of irritability and aggressivity. Language is poorly expressive with sparse use of sentences and insufficient word structures. Scholastic performances are poor. Episodes of encopresis and enuresis are persistent.

Case 2 (Interstitial 4q Deleted Region)

This 4-year-old boy is the first born of healthy unrelated parents. Family history is irrelevant. The mother complained of epileptic seizures to the age of 10 years. During pregnancy the mother suffered by gestosis. Oligohydramnios, fetal growth failure and poor fetal movements were reported. The boy was born at 32 weeks by cesarean section with a birth weight of 1,700 g, height of 46 cm, and OFC of 32 cm (all > 3rd percentile). Apgar score was 6 and 8 at one and five minutes. At birth the child was kept in an incubator for a week. Transfontanellar ultrasound was normal. In the first months of life, growth was slow but constant with delay in developmental milestones. At four months, his weight was 4,900 g, height of 58 cm, and OFC 39 (all between 3rd and 10th percentile). At 25 months, weight was 9,800 g (3rd percentile), height of 80 cm, (> 3rd percentile) and OFC 48.5 cm (25th percentile). At physical examination, the child showed minor craniofacial features consisting of rounded and very high forehead, symmetrical plagiocephaly, mild asymmetric face, small palpebral fissure, epicanthus, low-set ears, short nose with large nasal bridge and rounded tip, micro-retrognathia. Primary dentition was complete. The thumbs were bilaterally adducted and mobile with digital hyperlaxity. There was talipes equino varus. The child showed good cognitive and social functions but a marked speech delay and behavior was good. At the age of four years, weight was 12.7 kg (> 3rd percentile), height 93 cm (> 3rd percentile) and OFC 51 cm (70th percentile). Audiometric test and ophthalmologic examination were normal. Electrocardiogram, echocardiogram and brain MRI were normal as were the waking and sleeping electroencephalogram. Abdominal ultrasound displayed an accessory spleen 7 mm wide at the level of the splenic ileus. Routine laboratory analysis was normal including plasma and urinary amino acids, urine organic acids and transferring isoelectric focusing. At the last examination at the age of seven years, the clinical features of the child were unchanged. At primary school, he interacts well with the other children, but scholastic performance is poor.

Genetic Testing

Genomic DNA was isolated from peripheral blood of the probands and parents to analyze structural anomalies using Human Genome CGH Microarray Kit 8x60K performed according to the manufacturer’ s recommendations (Agilent Technologies, Santa Clara, CA). Data analysis was done by Cytogenomics (GRCh37assembly). For copy number variant (CNV) interpretation, publicly available patient data from the Database of Genomic Variants (DGV) (dgv.tcag.ca), DECIPHER web-based resource (decipher.sanger.ac.uk), CNV dataset from Clinical Genome Resource (clinicalgenome.org), and morbidity map of developmental delay [11] were used.

Case 1

aCGH analysis revealed a 329.6 Kb long deletion in the proband in the 4q32.3 region (164.703.186-165.032.803)x1, inherited from his healthy mother. Normal results were observed in the father. The deletion size of the CNV harboring a partial fragment of MARCHF1 (membrane associated ring-CH-type finger 1) gene (OMIM#513331), a member of the MARCH family of membrane-bound E3 ubiquitin ligases (Fig. 1).

Case 2

aCGH analysis revealed a 600.3 Kb long deletion in the proband in the 4q13.3-q21.1 region (71.655.407–78.016.622)x1. Normal results were obtained in the healthy parents (Fig. 1).

Analysis of clinical features of the children revealed a facial resemblance among them. Moreover, both showed a mild DD, marked speech delay, pre-postnatal growth retardation, adducted thumb positions and digital hyperlaxity. Diversities were noted with regard to behavioral disturbances and precocious, crowded dentition for Case 1 and an accessory spleen and talipes equino varus for Case 2 (Table 1).

The phenotype and the severity of the 4q deletions depend on the extent of the deletion, the deleted genes, the genes that are dosage-sensitive and the possible contribution of additional genetic rearrangements [2–3]. The most common phenotypic abnormalities in cases with 4q deletions are cognitive disability, growth retardation, hypotonia, hypertelorism, cardiac defects, and abnormalities in the respiratory tract [1–10]. The great variability and severity of congenital malformations and disorders related to the 4q deletion have been reported to affect different organs and in most cases the anomalies are complexes with various organs and body areas involved in the associations. Anomalies have been reported affecting the brain (ventriculomegaly, cortical atrophy and prominent ventricles, large occipital encephalocele) [12–14], eyes (bilateral hypermetropia, pigmentary retinal degeneration, microphthalmia) [15–18], cleft palate and Pierre Robin syndrome [3, 5, 7, 19–21], heart (enlarged right atrium and ventricle, small atrial septal defect, abnormal structure and function of both ventricles and double inferior vena cava, coarctation of the aorta and interventricular communication, both valvar pulmonic stenosis, cor triatriatum) [3, 8, 22–24], kidneys (duplicated left intrarenal collecting system, polycystic kidney, bilateral extrarenal pelvis dysplastic cystic kidneys) [3, 9, 24–26], genital defects [27], limb development disorder (irregularity of the outline of the distal phalanx of the 4th digit, rudimentary left thumb with absence of right thumb, bilateral absence of ulna) [28–31]. Craniofacial dysmorphism has frequently been reported with signs that are not specifically diagnostic [32–36], as well cognitive involvement [17, 37–41], deficit of growth [25, 34] and epileptic seizures [22, 25]. Other reported anomalies include congenital hearing impairment [18, 42], hypercalciuria and kidney calcification [43], familial combined hyperlipidemia [44], pain insensitivity [45] and bleeding diathesis [46]. Suwa and Momol report a boy with a proximal interstitial 4q deletion who developed psychomotor retardation, seizures, and a liver tumor with an increased serum alpha-fetoprotein and rapid growth [47].

Prenatal cases of 4q deletions have also been reported confirming the wide clinical variability of presentation of the 4q-deletion disorder [5, 18, 38]. Results of prenatal cases of chromosome 4 deletion were reported by Tidrenczel et al. [48] who collected 10 cases: three with interstitial and seven with terminal deletion. At a fetopathological and postnatal examination, facial dysmorphism was reported in six cases, 40% exhibited congenital heart defects (CHD) and digital anomalies and 30% had a cleft lip or palate. These abnormalities were equally observed for both interstitial and terminal deletions.

For a short period, two unrelated children were clinically followed, one carrying a 4q interstitial deletion, the other a terminal 4q deletion. Clinical features of children of the same age were compared and similarities and diversity were noted (Table 1). Lin et al. [5] reviewed 45 patients with 29 4q terminal deletions and 16 with interstitial deletions. These patients manifested identifiable phenotypes including abnormal skull shape, hypertelorism, cleft palate, apparently low-set abnormal pinnae, short nose with abnormal bridge, virtually pathognomonic pointed fifth finger and nail, congenital heart and genitourinary defects, moderate/severe mental retardation, poor postnatal growth, and hypotonia. Clinical features of the 29 patients with terminal 4q deletion and 16 patients with interstitial 4q deleted region were reported in association with those observed in the probands (Table 2). The authors noted that, in general, patients with various interstitial deletions proximal to 4q31 had a less specific phenotype, although DD and minor craniofacial anomalies were also present [5].

Table 1

Similarity and diversity reported in the probands: Case 1 with 4q terminal deletion and Case 2 with interstitial deletion.
	Case 1	Case 2
Diversity	Deletion in 4q32.3 region (164.703.186-165.032.803)x1.	Deletion in 4q13.3-q21.1 region (71.655.407–78.016.622)x1.
Diversity	Precocious and crowded dentition, behavioral disturbances.	Spleen accessory, talipes equino varus.
Similarity	Pre-postnatal growth delay, rounded and very high forehead, symmetrical plagiocephaly, asymmetric face, palpebral fissure small, epicanthus, short nose with large nasal bridge and rounded tip, microretrognathia, low-set ears, bilateral adducted thumbs with digital hyperlaxity. Mild DD with marked speech delay, infantile hypotonia.

Table 2

**Main clinical features of Case** 1 **and Case** 2 **and 29 patients showing terminal 4q deletion and 16 patients with interstitial 4q deleted region** [5]. The number is indicative of the patients involved in [5]; + present; - absent.
	Clinical features	Terminal [5]	Case 1	Interstitial [5]	Case 2
General features	Male/Female	13/16	M	5/11	M
	Birth weight > 3rd	4	+	6	+
	Gestation > 37th weeks	5	+	3	+
Craniofacial features	Abnormal skull	19	+	9	+
	Asymmetric face	5	+	1	+
	Palpebral fissures small	7	+	1	+
	Palpebral fissures upslanting	8	-	2	-
	Hypertelorism	14	-	6	-
	Epicanthal folds	10	+	7	+
	Short nose	16	+	2	+
	Abnormal nasal bridge	22	+	7	+
	Anteverted nares	12	-	3	-
	Cleft lip	8	-	1	-
	Cleft palate	23	-	3	-
	Microretrognathia	26	+	7	+
	Pierre Robin sequence	9	-	-	-
	Low ears, +/- set rotation	14	+	12	+
	Abnormal pinnae	18	-	12	-
Limbs	Absent digits	3	-	1	-
	Clinodactily	11	-	2	-
	Camptodactyly	5	-	-	-
	Abnormalities of thumb/hallux	12	+	-	+
	Tapering 5th finger	13	-	1	-
	Pointed/duplicated 5th nail	9	-	-	-
	Simian crease	15	-	6	-
	Absent/hypoplastic flexion crease	14	-	1	-
	Overlapping toes	8	-	3	-
Congenital heart defects		16	-	4	-
Hypotonia		10	+	8	+
Neurodevelopmental	Seizures	4	-	4	-
Developmental delay	Absent	2	-	-	-
	Mild	2	+	-	+
	Moderate/severe	19	-	14	-
Others	Postnatal growth failure	17	+	8	+/-
	Genitourinary defect	12	-	6	-
	Gastrointestinal defect	4	-	3	-

According to recent observations, interstitial and terminal 4q deletion are labeled under a common term “the 4q deletion syndrome” with main clinical manifestations consisting of craniofacial features, pre and postnatal growth failure, developmental delay, speech and language impairment, complex congenital heart defects (CHD), digital anomalies and pointed fifth finger and nail, with the latter indicated as pathognomonic diagnostic signs [5]. Strehle and Bantock [6] collected 101 cases of 4q deletion syndrome from the literature. They found the craniofacial feature a the most common anomaly and present in 99% of the cases, followed by digital (88%), skeletal (54%), and cardiac anomalies in 50% of the cases and an overall mortality of 28%. According to these authors, nearly all surviving patients presented with DD/ID and approximately two-thirds presented pre- and postnatal growth failure. In a subsequent report, Strehle et al. [7] noted that, although variable, the common spectrum of malformations in 4q deletion syndrome typically includes craniofacial, DD, digital, skeletal and cardiac anomalies. In this syndrome, other anomalies have been reported such as bilateral thumbs anomalies, left side hypoplasia, bilateral ptosis [2–3], erythroderma [29], ocular [18] and hearing impairment [42], ulnar defects [30–31] and occipital encephalocele [14].

Xu et al. [9] found ID (94%), likewise cleft palate and micrognathia (94%), craniofacial anomalies including broad nasal bridge (92%), post-natal growth deficiency (83%), digital anomalies mainly involving the fifth finger (50–88%), rotated ears (56%), and complex CHD (50%). Critical region anomalies of individuals with 4q deletion syndrome are reported by Strehle et al. [7] at 4q35.1 (465 Kb deletion) for orofacial cleft and CHD; by Xu et al. [9] at the 4q32.2-34.3 level (11.6 Kb deletion) for complex CHD by Maldzienè et al. [49] at 4q13.3 (1.56 Mb) for ID, growth retardation and CHD observed also in the mother and in two sibs with the same molecular anomaly. As a result of a combinatorial approach of conventional and genetic methods, the genotypic-phenotypic correlations depending on the breakpoint and size of terminal deletion have been characterized. This showed that in the 4q32 region there are a large number of genes presumably implicated in pathogenic phenotypes, associated with moderate or high pLI scores ‒meaning that the gene is intolerant for loss of function variations. In fact, some genes (HAND2, TLL1 and SORBS2) may have a stronger role in congenital heart defect [48]. As previously discussed by the authors for Case 1 [10], the effects of the loss of MARCHF1 gene, despite the low score of pLI (≤ 0.1), appeared to be implicated in neurodevelopmental delay and language impairment [50]. There is limited literature on 4q interstitial deletions because of its rarity and being phenotypically heterogenous. But interestingly, a recent study detecting the smallest interstitial deletion (1.56 Mb) and discussed three genes (ADAMTS3, ANKRD17 and COX18) also found in Case 2, thought to be candidate genes for intellectual disability, growth retardation and congenital heart defect [49].

In conclusion, the probands have been seen at the same age, in the same period of time and serially followed up from infancy to the age of seven years by two of the current authors (Piero Pavone, Raffaele Falsaperla). The two probands with different deletions (interstitial vs terminal deletion, 329.6 vs 600.3 Kb) showed similarity in some clinical expressions such as some craniofacial features, pre- and postnatal growth failure, speech and developmental delay and diversity such as precocious and crowded dentition in Case 1, and accessory spleen and talipes equino varus in Case 2.

Diversities were also found with regard to the classical manifestations of 4q deletion syndrome. It is difficult to explain the different clinical expressions in the children: the genes in these two areas may be functionally associated or may be deletions modifying chromosome structure, therefore affecting the expression of other genes correlated to the symptoms but outside the areas of interest. Signs presented by individuals with 4q deletion syndrome are in general not distinctive and a correct diagnosis may only arise following genetic investigation.

Ethics approval and consent to participate

The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki and was approved by the ethic committee of the University of Catania, Italy (Ethical Committee Catania 1 Clinical Registration n. 95/2018/PO). Written informed consent was obtained from the parents.

Consent for publication

The participant has consented to the submission of the case report to the journal.

Availability of data and material

Additional data used to support the findings of this study may be released upon application to the corresponding author who can be contacted at [email protected].

Competing interests

The authors declare that they have no competing interests.

Funding

There is no funding source.

Authors' contributions

Xena Giada Pappalardo and Piero Pavone drafted the present manuscript. Piero Pavone worked with and Raffaele Falsaperla helped gather patient data. Riccardo Lubrano, Alberto Verrotti, Pasquale Parisi and Piero Pavone revised the work critically for important intellectual content. All authors read and approved the final manuscript.

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Clinical comparison between terminal and interstitial 4q deletion in two unrelated children

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Abstract

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Introduction

Clinical Study

Case 1 (Terminal 4q deleted region)

Case 2 (Interstitial 4q Deleted Region)

Genetic Testing

Results

Discussion

Declarations

References

Additional Declarations

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