In 1994, the causative gene for ARPKD, PKHD1, was mapped to chromosome 6p12. However, only in recent years it was sequenced, allowing, thus, to achieve the genomic profile of the affected patients, as well as the differential diagnosis from other renal cystic diseases [10-13].
The majority of ARPKD patients are identified late in pregnancy or at birth. Even second trimester fetal US often fails to detect enlargement and/or increased echogenicity of both kidneys [10, 14], and oligohydramnios may be the only sign of the disease, as occurred in the present patient. Newborns with perinatally diagnosed massive renal enlargement have a poor prognosis, and usually die of respiratory problems within the first days of life [2, 15, 16].
The exceptionally rapid enlargement of the kidneys described in the present report, raises relevant questions about the pathogenic mechanisms underlying the disease. Specifically, the rare homozygous mutation of our proband showed to be particularly severe, as it is a nonsense variant, which inserts a stop codon within the amino acid sequence of the encoded protein (polyductin/fibrocystin, 4074 amino acids). Indeed, the PKHD1 transcript is interrupted at the amino acid 1775, and lacks its major part. This suggests a severe functional impairment of the protein, and may explain the clinical severity and the unfavorable outcome of the proposita. However, the serious clinical evolution of our newborn may also be related to other factors added to the PKHD1 genotype (as supported by the reported intrafamilial clinical variability among affected siblings) . It may also depend on other genetic and/or epigenetic factors . Thus, the severity of the disease is attributable to both modifier genes, and environmental factors. In our patient glycometabolic derangements, related to maternal diabetes, could have exerted deleterious effects both before conception, altering the biologic/molecular features of maternal germinal cells, and during embryo-fetal development [2, 18, 19].
From a biochemical/molecular point of view, it has been supposed that proteins, like the epidermal growth factor receptor (EGFR), are abnormally expressed in the cystic renal epithelia of such patients. Their increased expression is associated with epithelial hyperplasia, leading to progressive enlargement of cysts . Moreover, in these subjects it has been observed an increased activation of the mTOR (mechanistic target of rapamycin kinase) signaling pathway . Both mechanisms, shared with other diseases, might explain the extremely high level of proliferation of the cystic epithelia, which led to the severe phenotype in our patient as well as in those with overlapping clinical features. Also, pulmonary hypertension, reported in some ARPKD patients  and present in our newborn, may recognize such biochemical/molecular alterations. Thus, it may be associated, aside from the condition of chronic hypoxia, with endothelial dysfunction and hypercontraction of vascular smooth muscle cells .
Despite recent advances in neonatal care, genetic knowledge, and excellent outcomes for pediatric kidney transplant, the 1-year mortality is still to date around 30% , and more often related to pulmonary hypoplasia, rather than to renal insufficiency . MV is a strong negative predictor of long-term survival, and patients who need ventilator support, like our newborn, show a higher mortality rate than those who develop hypertension, progressive renal insufficiency, and portal tract fibrosis .
Unilateral or bilateral nephrectomy, with subsequent peritoneal dialysis, have been reported as therapeutic approach for selected subjects .
The management of the severely affected neonates, therefore, focuses on MV and, occasionally, on unilateral or bilateral nephrectomy . Indeed, early removal of both fast-growing kidneys, pre-emptive peritoneal dialysis, since haemodialysis may be considered only when the peritoneal one is impossible to perform , and kidney transplantation, may be the most promising option in patients with respiratory impairment due to increased peri/postnatal growth of the kidneys . However, the risk of accelerating renal function loss, and the consequent need for renal replacement therapy early in life, must be carefully weighed [3, 22]. In our patient, the fulminant worsening of the clinical conditions did not allow for an effective treatment plan. Indeed, the present patient shows some of the clinical and bioethical issues, also related to the difficulties encountered due to cultural and linguistic differences, which may arise in the management of ARPKD newborns.
This patient report may provide further insights into the molecular pathogenesis of ARPKD, as well as a better genomic and clinical characterization of the disease. The study of new patients will allow to outline further genotype-phenotype correlations .
The hope for the next future may come from the ever-deeper knowledge of the underlying genomic/molecular mechanisms, which may lead to effective therapies  (i.e. the inhibition of mTOR to attenuate the growth of cystic epithelium, potentially useful also for other pathologies) [25, 26].
Meanwhile, the role played by next generation sequencing (NGS) techniques is becoming increasingly precious and determinant. These methods, providing precise genomic information, make the use of invasive investigations, like renal biopsy in ARPKD, no longer necessary, and allow to define more accurate prognoses. Indeed, when promptly obtained, they may guide and support clinicians and guarantee to the patients the most appropriate clinical management, avoiding futile and/or disproportionate treatments, as well as further unnecessary separations between children and their parents . Then, in critical situations, as in our patient, the attention may shift from the invasive approach to a different goal, which is the reduction in suffering.