Sudden unexpected postnatal collapse and BUB1B mutation: first forensic case report

SUPC is defined as the collapse of the clinical conditions of a term or near-term newborn, in good clinical condition, who has an Apgar score > 8 at the tenth minute and who, suddenly and unexpectedly, manifests apnea, acute cyanosis or paleness, requiring resuscitation support characterized by cardio-pulmonary resuscitation with, more or less, oro-tracheal intubation [20]. The British Association of Perinatal Medicine has defined SUPC as a sudden collapse of the clinical condition of the full-term or near-term newborn, who, within the first 7 days of life, assigned to routine postnatal care, requires resuscitation with positive ventilation and who either dies, or has hypoxic-ischemic encephalopathy, or requires intensive care in an NICU [21].

Most cases of SUPC occur within the first 24 h of life: 36% within the first 2 h after birth, 29% between 2 and 24 h after birth, while 24% occur between 24 and 72 h after birth and 9% between the 4th and 7th day of life. There are only approximately 2,000 cases described in the literature reporting a widely varying incidence of SUPC, with estimates ranging from 1.92 per 100,000 live births to 38 per 100,000. The prognosis is, most of the time, negative, with a mortality rate of 50% of cases and, with the same frequency, they are inexplicable [1, 22].

The timing of SUPC onset is very varied, some authors maintain that it develops in the first 24 h of life, others, however, maintain from 0 to 7 days of life, others, such as Becher et al. [23] stated that the manifestation appears within the first two hours of life in 73% of cases. A recent article reported five cases of SUPC in which all the newborns were full-term (36 to 38 weeks of gestation), born by vaginal delivery (4 cases) or by cesarean Sect. (1 case), with a collapse that occurred within 2.5 h of birth [24].

In the present clinical case, the newborn was born from a full-term pregnancy (38 + 2 weeks of gestation), with an Apgar score of 10/5 and a sudden collapse of clinical conditions 2 h after birth. Therefore, according to the criteria established by the guidelines [21], a diagnosis of SUPC was established.

One of the most common risk factors is uncontrolled skin-to-skin contact between the mother and newborn. In fact, during the first breastfeeding there is skin-to-skin contact between mother and newborn in the prone position [5]. According to some studies, however, it has not yet been clarified that this could lead to a risk factor for SUPC due to the asphyxial mechanism, in fact, some authors recommend carrying out nursing monitoring in this phase [24]. Even unmonitored skin-to-skin contact can constitute a risk factor, very little is known about the etiology of SUPC, which most of the time remains unknown, as newborns do not have problems related to prematurity and low Apgar scores at birth [20]. Becher et al. [23] state, in fact, that SUPC is rare in any center and there is no standard approach to investigations. In cases where collapse is not due to an underlying abnormality, breastfeeding and prone positioning are important associations.

In the present study, a diagnosis of SUPC was made through retrospective analysis of the medical records. Then a complete autopsy was performed showing the findings of an HIE with bronchopulmonary septic emboli. Finally, a complete genetic analysis was made that showed a mutation in the BUB1B gene.

Regarding the autopsy and histopathological-forensic findings of the outcomes of a HIE, it is consistent with other studies, since many of the newborns with SUPC die from hypoxic-ischemic encephalopathy. Indeed, Pejovic NJ et al. [7], showed that out of 26 cases of SUPC, 5 had HIE treated by hypothermia. However, to date, there are no published case reports in which a complete autopsy of a newborn with SUPC was performed, this, in fact, would be the first.

However, the finding of the BUB1B mutation has been identified for the first time. There are no studies that correlate the mutation of the BUB1B gene with SUPC, so it is not possible to establish a causal relationship between the two events, but it is important to report this to the scientific community.

Mutations in the BUB1B gene are associated with MVA1 and involve different chromosomes and tissues. MVA1 is typically related to problems during pregnancy (IUGR), neonatal (postnatal growth retardation and severe neurological damage including microcephaly) and development (developmental delay/cognitive disability, epileptic seizures and generalized hypotonia, different types of neoplasms) [25]. In mice, mutations in the BUB1B gene cause the onset of oncogenesis. A surveillance mechanism linking loss of BUB1B to the activation of the p53 pathway, promoting oncogenesis, has recently been reported [26]. Specifically, the most frequently encountered neoplasms are colorectal cancer, lung cancer, pancreatic cancer, but also thyroid follicular adenoma, leukemia, and glioblastoma [27‐30]. A recent study also correlated the mutation of the BUB1B gene with the onset of pediatric neuroblastoma, bladder cancer, breast cancer, and endometrial carcinoma [31‐34]. A published case report giving the clinical history of an Italian girl with a karyotype showing 12% mosaics with a new variant of the BUB1B gene (c.2679 A > T, p.Arg893Ser). The girl was two years old and presented with severe neurological disorders, microcephaly and epileptic seizures [35]. Another case report involved a child who, at 6 months of age, showed severe developmental delay, microcephaly, hypotonia, intractable seizures including infantile spasms with hypsarrhythmia, and Dandy-Walker malformation on MRI. Notably, the seizures were resistant to antiepileptic therapy and adrenocorticotropic hormone treatment. The authors concluded that knowledge of this genetic disease is important not only for a correct diagnosis but also for family genetic counseling [36]. In the present case, in fact, the child’s parents were informed during the hospital stay of the possible reappearance of the same mutation in future pregnancies, clarifying the possibility to perform a prenatal diagnosis.

In this manuscript, SUPC was followed by a 5-month hospitalization in which the infant experienced numerous healthcare-related infections from various microorganisms, including Staphylococcus epidermidis, Staphylococcus Homini, Candida Albicans, and Klebsiella Pneumoniae. Blood cultures were negative for Pneumocystis carinii. The infectious picture was also demonstrated through CT and chest x-ray. However, these infections were treated with appropriate antibiotics after susceptibility testing. After 5 months, laboratory tests were normal and the child did not have any infection but only bacterial contamination. The pulmonary findings examined showed pulmonary bulae. However, it would appear that bulae are attributable more to the long duration of hospitalization and the outcomes of nosocomial pulmonary infections, rather than to the genetic BUB1 mutation. Also Fig. 2 shows “hyphae” attributable to Candida Albicans infection.

The present case report showed the heterozygous compound variants in the BUB1B gene, which, at the protein level, result in the introduction of the premature stop codon and the amino acid change. Although the first mutation can be classified according to ACMG guidelines as a pathogenic variant, the other mutation can be classified as a VUS. In this scenario, it is not possible to demonstrate the causal effect of this mutation, considering that it could play a causal or concausal role in the onset of SUPC.

However, due to the rarity of the two pathologies (BUB1B mutation and SUPC), their relationship can be hypothesized but is not certain. Therefore, the aim of this case report is to inform the scientific community of a possible correlation between the two conditions, indicating that further studies are needed to confirm this. Moreover, in newborns who die from or following a SUPC it is necessary to perform an autopsy or a hospital autopsy complete with genetic investigation, as important elements could emerge capable of contributing to the knowledge of both the SUPC and the BUB1B mutation as well as the possible correlation between these two.