DiGeorge Syndrome in newborns conceived from assisted reproductive techniques: is preimplantation screening necessary? A discussion of two cases

Abstract

Background

Assisted reproductive techniques are increasingly common, necessitating optimized genetic testing for embryos to reduce congenital disease risks. DiGeorge syndrome (DGS) is a severe genetic condition linked to complex congenital heart diseases and immunological issues. Reports of DGS in newborns conceived via intracytoplasmic sperm injection (ICSI) are scarce, with only two documented cases, one leading to pregnancy termination after diagnosis in the embryo.

Case presentation

Case 1 is a full-term female newborn from an ICSI conception, born without a prenatal diagnosis. She exhibited hypotonia, hypocalcemia, seizures, and features of DGS, alongside congenital heart disease due to interrupted aortic arch. Surgical repair was successful, and she required calcium and anticonvulsant therapy upon discharge. Case 2 is a preterm male newborn, also conceived via ICSI in a surrogate, presenting with cyanosis, hypotonia, and other abnormalities. He was diagnosed with Tetralogy of Fallot and hypocalcemia, undergoing surgical correction at 6 months. Both cases had follow-ups at one year, showing no complications and confirmed DGS diagnoses.

Conclusions

DGS poses significant risks for newborns, including heart defects. Given its limited association with assisted reproductive techniques, preimplantation genetic screening should be considered, particularly for families with a history of DGS and concerning findings in embryos.

Background

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans and is associated with congenital anomalies and additional health problems. The syndrome has an incidence of live births of 1 in 2148 [1] and 1 in 1497 in spontaneous abortions, [2] regardless of maternal age. In recent studies, a 22q11.2 deletion was found in 1 in 19 pregnancies undergoing genetic testing for cardiac anomalies and 1 in 93 for all indications [3].

Mortality rates range from 5 to 10% [4, 5], with a correlation to the severity of immune compromise and congenital heart disease, the latter being present in 60% of cases [6]. Confirmatory diagnosis involves ligand-dependent probe amplification (MLPA) or fluorescent in situ hybridization (FISH) of the affected region [7], and it can be performed prenatally and/or during preimplantation [8, 9]. Assisted reproductive technology (ART) increases the risk of congenital anomalies [10, 11], although the evidence linking it to DGS is limited [12, 13]. The indication for prenatal and preimplantation screening for chromosomal anomalies in ART is still debated [14, 15]. Performing preimplantation genetic testing poses a higher risk of gestational failure and is recommended only based on known genetic history or Mendelian inheritance patterns [16]. This article presents two cases of newborns with congenital heart disease and DGS without prenatal diagnosis, comparing them with published cases of DGS in ART. The discussion revolves around the use of genetic screening for preimplantation DGS due to the implications of this genetic anomaly on the morbidity and mortality of newborns.

Case presentation

Case 1

A term female newborn delivered at 39.5 weeks, weighing 3670 g, conceived from in vitro fertilization using intracytoplasmic sperm injection (ICSI). The pregnancy ocurred in a 41-year-old primigravida woman, whitin a non-consanguineous parents, both healthy and with no relevant family history. No prenatal diagnosis of congenital anomalies was made in this case, possibly due to the presence of a patent ductus arteriosus, which can mask the interruption of the aortic arch in fetal circulation.

The delivery was via cesarean section due to a failed induction, and the neonate exhibited poor adaptation, requiring invasive mechanical ventilation due to respiratory distress. Physical examination revealed generalized hypotonia, hypoplasia of the depressor muscle of the mouth angle, a long face, small mouth, asymmetrical and square-shaped ears, palpebral fissures, a long filtrum, tubular nose, and long fingers. An echocardiogram and chest angiotomography were performed, revealing interruption of the aortic arch type-B1, perimembranous ventricular septal defect, and aberrant right subclavian artery (Image 1). The newborn experienced seizures with the electroencephalogram reporting ictal activity in the right temporal focal region with moderate frequency. Additional tests showed persistent hypocalcemia, moderate lymphopenia, moderate thrombocytopenia, and a chest X-ray with the absence of thymic silhouette.

Image 1.

Chest angiotomography with aortic reconstruction showing interrupted aortic arch with the presence of ductal arch (*) and aberrant left subclavian artery (ALSA)

Surgical correction involved aortic arch plasty, closure of the perimembranous ventricular septal defect with a patch, and reimplantation of the right subclavian artery to the right carotid artery. A reintervention was necessary on the third postoperative day for ascending aorta enlargement, followed by epicardial pacemaker implantation due to complete AV block. The clinical course was satisfactory, and at 1 year old, the infant is asymptomatic, on oral calcium supplementation. FISH analysis confirmed the diagnosis of DiGeorge Syndrome: (46, XX.ish del (22), (q11.2q11.2) (TUPLE1), (22) q13.3) (SHANK3 × 2) [400] (Image 2A).

Image 2.

FISH analysis results confirming 22q11.2 deletion.  FISH analysis showing 22q11.2 deletion in case 1 (left) and case 2 (right). Absence of the TUPLE1 signal indicates deletion of the critical region

Case 2

A preterm male newborn, conceived through in vitro fertilization using intracytoplasmic sperm injection (ICSI) and carried in a surrogate uterus, was delivered at 34.5 weeks of gestation due to premature rupture of membranes, with a weighing 2695 g. The father was a 48-year-old smoker with no previous children, and the mother was 23 years old with two prior uncomplicated pregnancies. Both parents were apparently healthy and with no family history. Prenatal diagnosis was not performed due to limited access to obstetric ultrasound and specialized prenatal care during the surrogate pregnancy.

Physical examination revealed cyanosis, hypotonia in the limbs, symmetric palpebral fissures, normally positioned winged auricles, low nasal bridge, micrognathia, symmetric short neck, hypoplasia of the proximal phalanx of the fifth bilateral finger, left cryptorchidism, and umbilical and epigastric hernia. The newborn was diagnosed with Tetralogy of Fallot (TOF) with moderate subvalvular stenosis on echocardiogram, without hemodynamic repercussions. No structural brain abnormalities were observed, and the electroencephalogram showed no seizure activity. Additional tests revealed persistent hypocalcemia and hypothyroidism. Surgical correction of congenital heart disease was performed at six months of age without complications. FISH analysis confirmed the diagnosis of DiGeorge Syndrome: 22q11.2 (D22S75 × 1), 22q13.3 (D22S1254 × 2) [100] (Image 2B).

Discussion

CHD in DGS often includes conotruncal pathologies such as truncus arteriosus, interrupted aortic arch, and Tetralogy of Fallot (TOF) [6], as seen in our two cases. The interruption of the aortic arch poses a prenatal diagnostic challenge due to the presence of the ductus arteriosus; however, there are subtle indirect ultrasound signs secondary to arch pathology, including cavity disproportion, mitral or aortic valve insufficiency, increased velocities, and aliasing in the aortic arch [17]. CHD is the leading cause of death in DGS, increasing the risk of mortality in the first year by up to three times compared to those without CHD [18, 19]. Early prenatal diagnosis of CHD, therefore, improves prognosis and supports neonatal management, planning elective delivery in a specialized center [6, 20]. This relies on clinical history, pathological history of the pregnant woman, and sequential obstetric ultrasound assessments from weeks 11–14 of gestation, with detailed anatomical ultrasound at weeks 20–22. In case of any suspicion of cardiac or structural anomalies, it should be complemented with fetal echocardiography, with a sensitivity close to 95% [21]. Fetal echocardiography is indicated for pregnancies resulting from ART [22], regardless of the specific technique used.

Indications for prenatal genetic testing for 22q11.2 deletion syndrome (22q11.2DS) include a family history of one parent or a previous child with the 22q11.2 microdeletion or suggestive findings on fetal ultrasound. The American College of Obstetricians and Gynecologists (2020) supports the use of preimplantation genetic testing (PGT) in in ART cases involving a known pathogenic variant, a previously affected offspring, or other specific indications [14]. For 22q11.2 deletions, PGT can be performed via FISH or chromosomal microarray techniques [8, 9, 15].

Our two cases illustrate this diagnostic gap. In Case 1, no prenatal diagnosis was made, likely due to the anatomical features of the defect. In Case 2, no diagnosis was established due to limited access to prenatal imaging during a surrogate pregnancy. These situations underscore the importance of comprehensive prenatal screening, particularly in ART-conceived pregnancies. When conotruncal defects are detected—or when screening access is limited—testing for 22q11.2DS should be considered to guide perinatal management.

ART is associated with an increased risk of congenital anomalies, including some forms of CHD. This may be due not only to the techniques used (such as ICSI) but also to characteristics of the parents. Many women undergoing ART are of advanced maternal age or have other predisposing factors [23, 24]. Preimplantation or prenatal diagnosis for anomalies such as CHD or 22q11.2DS should be evaluated on a case-by-case basis, especially in the presence of Mendelian inheritance patterns, advanced parental age, or family history of genetic syndromes, among others [12]. Additionally, increased parental age and smoking have been associated with a higher rate of de novo mutations and genomic instability [25–27]. Although a direct association with 22q11.2 deletions has not been conclusively demonstrated, these paternal factors may support the decision for genetic counseling and targeted testing in ART pregnancies.

Despite the increasing use of ART, the occurrence of 22q11.2DS in this context remains rare. Only two cases have been reported in the literature (Table 1), one of which led to pregnancy termination following prenatal diagnosis. Both involved ICSI, as in our cases. Thus, while ART itself cannot be considered a sole risk factor for DGS or CHD, the combination of ART with other parental or fetal risk factors justifies a more tailored diagnostic approach.

Table 1.

Clinical characteristics of the patient compared to other patients with SDG conceived with ART

	Case 1	Case 2	Gollo, 2015 (10)
Gender	Female	Male	Female
Weeks at birth	39.5	34.5	36
Parental consanguinity	No	No	No
Congenital heart disease	Interrupted aortic arch + aberrant subclavian artery + ventricular septal defect	TOF	Common arterial trunk
Hypotonia	+	+	+
Symmetric face	+	+	+
Palatal anomalies			+
Hearing loss			+
Velopharyngeal insufficiency			+
Low oral commissure	+		+
Long and slender fingers	+		+
Hypocalcemia	+	+	+
Lymphopenia	+	+
Thrombocytopenia	+
Thymic anomaly	+		+

TOF Tetralogy of Fallot

Following the postnatal diagnosis, genetic counseling was offered to both families in our report. However, no parental genetic testing was performed to determine whether the deletions were inherited or de novo, as there was no family history or clinical suspicion of 22q11.2DS prior to birth. This reflects a broader issue: many adults with 22q11.2DS remain undiagnosed and may not receive preconception counseling or be offered PGT. Due to the phenotypic variability of 22q11.2DS and its implications from birth through adulthood, long-term follow-up and interdisciplinary management are essential. Genetic testing of both parents may be warranted to assess recurrence risk, as inherited deletions are present in 10–15% of cases.

The discussion focuses on cases of ART with a mother without pathological history. ART cannot be considered a sole risk factor for CHD and DGS, so the decision to undergo prenatal or preimplantation genetic testing should be made individually, considering test availability, comorbidities, pathological history, and findings during prenatal care. It is necessary to focus ART studies on actively searching for risk factors and genetic syndrome histories. Preimplantation genetic testing (PGT_SR) for a fertilized embryo through ICSI is available, but it should be considered in specific cases based on family history. The challenges in 22q11.2 deletion syndrome (22q11.2DS) include variability in the phenotype and health issues that arise from before birth into adulthood, as is the case with many genetic disorders.

Author contribution

FR contributed to the description of the cases and literature search, LA to the structuring of the discussion and introduction, and CR to the construction of the discussion. NSD made genetic interpretation and discussion improvement. All authors read and approved the final manuscript.

Funding

No funds, grants, or other support was received.

Data availability

Data not available—participant consent.

Declarations

Ethics approval

The case report was approved by the Ethics Committee of the Fundación Cardiovascular de Colombia (CEI-2024–09070).

Consent to participate

Written informed consent and consent to publish were obtained from the parents.

Competing interests

The authors declare no competing interests.