Advances for pediatricians in 2022: allergy, anesthesiology, cardiology, dermatology, endocrinology, gastroenterology, genetics, global health, infectious diseases, metabolism, neonatology, neurology, oncology, pulmonology.

The last year saw intensive efforts to advance knowledge in pediatric medicine. This review highlights important publications that have been issued in the Italian Journal of Pediatrics in 2022. We have chosen papers in the fields of allergy, anesthesiology, cardiology, dermatology, endocrinology, gastroenterology, genetics, global health, infectious diseases, metabolism, neonatology, neurology, oncology, pulmonology. Novel valuable developments in epidemiology, pathophysiology, prevention, diagnosis and treatment that can rapidly change the approach to diseases in childhood have been included and discussed.

Report and follow-up on two new patients with congenital mesoblastic nephroma.

BACKGROUND: Tumors are rare in neonatal age. Congenital mesoblastic nephroma (CMN) is a usually benign renal tumor observed at birth, or in the first months of life. It may also be identified prenatally and associated with polyhydramnios leading to preterm delivery. Effective treatment is surgical in most cases, consisting in total nephrectomy. In literature, very few studies report on the neonatal management of such a rare disease, and even less are those describing its uncommon complications. CASES PRESENTATION: We report on two single-center newborns affected with CMN. The first patient is a preterm female baby, born at 30+ 1 weeks of gestation (WG) due to premature labor, with prenatal (25 WG) identification of an intra-abdominal fetal mass associated with polyhydramnios. Once obtained the clinical stability, weight gain, instrumental (computed tomography, CT, showing a 4.8 × 3.3 cm left renal neoformation) and histological/molecular characterization of the lesion (renal needle biopsy picture of classic CMN with ETV6-NTRK3 translocation), a left nephrectomy was performed at 5 weeks of chronological age. The following clinical course was complicated by intestinal obstruction due to bowel adherences formation, then by an enterocutaneous fistula, requiring multiple surgical approaches including transitory ileo- and colostomy, before the conclusive anastomoses intervention. The second patient is a 17-day-old male term baby, coming to our observation due to postnatal evidence of palpable left abdominal mass (soon defined through CT, showing a 7.5 × 6.5 cm neoformation in the left renal lodge), feeding difficulties and poor weight gain. An intravenous diuretic treatment was needed due to the developed hypertension and hypercalcemia, which regressed after the nephrectomy (histological diagnosis of cellular CMN with ETV6-NTRK3 fusion) performed at day 26. In neither case was chemotherapy added. Both patients have been included in multidisciplinary follow-up, they presently show regular growth and neuromotor development, normal renal function and no local/systemic recurrences or other gastrointestinal/urinary disorders. CONCLUSIONS: The finding of a fetal abdominal mass should prompt suspicion of CMN, especially if it is associated with polyhydramnios; it should also alert obstetricians and neonatologists to the risk of preterm delivery. Although being a usually benign condition, CMN may be associated with neonatal systemic-metabolic or postoperative complications. High-level surgical expertise, careful neonatological intensive care and histopathological/cytogenetic-molecular definition are the cornerstones for the optimal management of patients. This should also include an individualized follow-up, oriented to the early detection of any possible recurrences or associated anomalies and to a better quality of life of children and their families.

Intestinal malrotation in a female newborn affected by Osteopathia Striata with Cranial Sclerosis due to a de novo heterozygous nonsense mutation of the AMER1 gene.

BACKGROUND: Osteopathia Striata with Cranial Sclerosis (OS-CS), also known as Horan-Beighton Syndrome, is a rare genetic disease; about 90 cases have been reported to date. It is associated with mutations (heterozygous for female subjects and hemizygous for males) of the AMER1 gene, located at Xq11.2, and shows an X-linked pattern of transmission. Typical clinical manifestations include macrocephaly, characteristic facial features (frontal bossing, epicanthal folds, hypertelorism, depressed nasal bridge, orofacial cleft, prominent jaw), hearing loss and developmental delay. Males usually present a more severe phenotype than females and rarely survive. Diagnostic suspicion is based on clinical signs, radiographic findings of cranial and long bones sclerosis and metaphyseal striations, subsequent genetic testing may confirm it. CASE PRESENTATION: Hereby, we report on a female newborn with frontal and parietal bossing, narrow bitemporal diameter, dysplastic, low-set and posteriorly rotated ears, microretrognathia, cleft palate, and rhizomelic shortening of lower limbs. Postnatally, she manifested feeding intolerance with biliary vomiting and abdominal distension. Therefore, in the suspicion of bowel obstruction, she underwent surgery, which evidenced and corrected an intestinal malrotation. Limbs X-ray and skull computed tomography investigations did not show cranial sclerosis and/or metaphyseal striations. Array-CGH analysis revealed normal findings. Then, a target next generation sequencing (NGS) analysis, including the genes involved in skeletal dysplasias, was performed and revealed a de novo heterozygous nonsense mutation of the AMER1 gene. The patient was discharged at 2 months of age and included in a multidisciplinary follow-up. Aged 9 months, she now shows developmental and growth (except for relative macrocephaly) delay. The surgical correction of cleft palate has been planned. CONCLUSIONS: Our report shows the uncommon association of intestinal malrotation in a female newborn with OS-CS. It highlights that neonatologists have to consider such a diagnosis, even in absence of cranial sclerosis and long bones striations, as these usually appear over time. Other syndromes with cranial malformations and skeletal dysplasia must be included in the differential diagnosis. The phenotypic spectrum is wide and variable in both genders. Due to variable X-inactivation, females may also show a severe and early-onset clinical picture. Multidisciplinary management and careful, early and long-term follow-up should be offered to these patients, in order to promptly identify any associated morbidities and prevent possible complications or adverse outcomes.

New insights in pediatrics in 2021: choices in allergy and immunology, critical care, endocrinology, gastroenterology, genetics, haematology, infectious diseases, neonatology, neurology, nutrition, palliative care, respiratory tract illnesses and telemedicine.

In this review, we report the developments across pediatric subspecialties that have been published in the Italian Journal of Pediatrics in 2021. We highlight advances in allergy and immunology, critical care, endocrinology, gastroenterology, genetics, hematology, infectious diseases, neonatology, neurology, nutrition, palliative care, respiratory tract illnesses and telemedicine.

Congenital hypopituitarism and multiple midline defects in a newborn with non-familial Cat Eye syndrome.

BACKGROUND: Cat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2). CASE PRESENTATION: We report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis. CONCLUSIONS: CES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

Cardio-facio-cutaneous syndrome and gastrointestinal defects: report on a newborn with 19p13.3 deletion including the MAP 2 K2 gene.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) belongs to RASopathies, a group of conditions caused by mutations in genes encoding proteins of the rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathway. It is a rare syndrome, with about 300 patients reported. Main clinical manifestations include facial dysmorphisms, growth failure, heart defects, developmental delay, and ectodermal abnormalities. Mutations (mainly missense) of four genes (BRAF, MAP 2 K1, MAP 2 K2, and KRAS) have been associated to CFCS. However, whole gene deletions/duplications and chromosomal microdeletions have been also reported. Specifically, 19p13.3 deletion including MAP 2 K2 gene are responsible for cardio-facio-cutaneous microdeletion syndrome, whose affected subjects show more severe phenotype than CFCS general population. CASE PRESENTATION: Hereby, we report on a female newborn with prenatal diagnosis of omphalocele, leading to further genetic investigations through amniocentesis. Among these, array comparative genomic hybridization (a-CGH) identified a 19p13.3 microdeletion, spanning 1.27 Mb and including MAP 2 K2 gene. Clinical features at birth (coarse face with dysmorphic features, sparse and friable hair, cutaneous vascular malformations and hyperkeratotic lesions, interventricular septal defect, and omphalocele) were compatible with CFCS diagnosis, and further postnatal genetic investigations were not considered necessary. Soon after discharge, at around 1 month of life, she was readmitted to our Neonatal Intensive Care Unit due to repeated episodes of vomiting, subtending a hypertrophic pyloric stenosis (HPS) which was promptly identified and treated. CONCLUSIONS: Our report supports the 19p13.3 microdeletion as a contiguous gene syndrome, in which the involvement of the genes contiguous to MAP 2 K2 may modify the patients' phenotype. It highlights how CFCS affected subjects, including those with 19p13.3 deletions, may have associated gastrointestinal defects (e.g., omphalocele and HPS), providing further data on 19p13.3 microdeletion syndrome, and a better characterization of its genomic and phenotypic features. The complex clinical picture of such patients may be worsened by additional, and even precocious, life-threatening conditions like HPS. Clinicians must consider, anticipate and/or promptly treat possible medical and surgical complications, with the aim of reducing adverse outcomes. Extensive diagnostic work-up, and early, continuous, and multidisciplinary follow-up, as well as integrated care, are necessary for the longitudinal clinical evolution of any single patient.

Hypertrophic pyloric stenosis masked by kidney failure in a male infant with a contiguous gene deletion syndrome at Xp22.31 involving the steroid sulfatase gene: case report.

BACKGROUND: Contiguous gene deletion syndrome at Xp22.3 resulting in nullisomy in males or Turner syndrome patients typically encompasses the steroid sulfatase gene (STS) and contiguously located other genes expanding the phenotype. In large deletions, that encompass also the Kallmann syndrome 1 gene (KAL1), occasionally infantile hypertrophic pyloric stenosis (IHPS) and congenital anomalies of the kidney and urinary tract (CAKUT) have been reported. PATIENT PRESENTATION: We report on a male newborn with family history in maternal uncle of renal abnormalities and short stature still without ichthyosiform dermatosis. The baby presented CAKUT with kidney failure and progressive vomiting. Renal bicarbonate loss masked hypochloremic and hypokalemic metabolic alkalosis classically present in IHPS and delayed its diagnosis. Antropyloric ultrasound examination and cystourethrography were diagnostic. After Fredet-Ramstedt extramucosal pyloromyotomy feeding and growing was regular and he was discharged home. Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene. CONCLUSIONS: Aberrant cholesterol sulfate storage due to STS deletion as the underlying pathomechanism is not limited to oculocutaneous phenotypes but could also lead to co-occurrence of both IHPS and kidney abnormalities, as we report. Thus, although these two latter pathologies have a high incidence in the neonatal age, their simultaneous association in our patient is resembling not a chance but a real correlation expanding the clinical spectrum associated with Xp22.31 deletions.

Case Report: Unusual Clinical Presentation of a Rare Cardiac Inflammatory Myofibroblastic Tumor in Children: The Differential Diagnosis With Pediatric Emergencies.

Introduction: There are still no guidelines about pediatric cardiac cancers. The purpose of this work is to provide new scientific data facilitating the differential diagnosis of a rare cardiac tumor with an unusual presentation, such as the cardiac inflammatory myofibroblastic tumor (IMT). Case Presentation: A 3-year-old male child presented with several symptoms including unconsciousness, vomiting, and drowsiness. A clinical and neurological examination revealed a unilateral (right) motor delay and positive unilateral Babinski sign. Electrocardiogram (ECG) was normal. Diagnostic Assessment: The total body computed tomography (CT) scans showed hypodensity in the left temporal-parietal lobe, a large hypodense area in the right frontal lobe, and a second area in the left frontal lobe were found with head CT. A magnetic resonance (MR) also noted cerebral areas of hypointensity. The echocardiographic images revealed an ovoid mass, adherent to the anterolateral papillary muscle. The histological exams, performed with hematoxylin-eosin, Masson's trichrome, Alcian blue PAS, Weigert and Van-Gieson stain, allowed observing the microscopic structure of the neoplastic mass. The immunohistochemical analysis was performed through subsequent antibodies: anti-vimentin, anti-actina, anti-ALK, anti-CD8, anti-CD3, anti-CD20, anti-kappa and lambda chains, and anti CD68 antibodies. The healthcare professionals diagnosed a cardiac IMT with brain embolism. Differential Diagnosis: The ventricular localization, observed through radiological exams, required a differential diagnosis with fibroma and rhabdomyoma, the presence of brain embolism with sarcoma, and its morphology with fibroma. Neurological symptoms might be attributed to encephalitis, primitive cerebral cancer, such as astrocytoma or neuroblastoma, cerebral metastases due to any malignancy, or embolic stroke. Conclusion: New studies are encouraged to better define IMT behavior and draw up guidelines confirming the crucial role of multidisciplinary approach and treatment protocol selected on the basis of the characteristics of the tumors, in the case of this rare type of cancer.

Novel missense mutation of the TP63 gene in a newborn with Hay-Wells/Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome: clinical report and follow-up.

INTRODUCTION: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, is a rare genetic syndrome with ectodermal dysplasia. About 100 patients have been reported to date. It is associated to a heterozygous mutation of the tumor protein p63 (TP63) gene, located on chromosome 3q28. Typical clinical manifestations include: filiform ankyloblepharon adnatum (congenital adherence of the eyelids), ectodermal abnormalities (sparse and frizzy hair, skin defects, nail alterations, dental changes and hypohidrosis), and cleft lip/palate. Diagnostic suspicion is based on clinical signs and confirmed by genetic testing. PATIENT'S PRESENTATION: We hereby report on a female newborn with erythroderma, thin lamellar desquamations, extensive skin erosions, sparse and wiry hair, filiform ankyloblepharon adnatum, agenesis of the lachrymal puncta, cleft palate and nail dysplasia. Her phenotype was compatible with AEC syndrome. Then, based on the clinical suspicion, sequencing analysis of the TP63 gene was performed, and revealed a de novo novel missense mutation. Eyelids adherence and cleft palate underwent surgical correction, while skin erosions were treated with topical antibiotics/antifungals and emollient/re-epithelizing creams. A surgical reconstruction is presently planned for the agenesis of the lachrymal puncta. The infant currently is 17 months of age and is included in a multidisciplinary follow-up. At present shows growth impairment and mild developmental delay, and typical signs of ectodermal dysplasia with small areas of dermatitis lesions on the scalp, without further abnormalities. CONCLUSIONS: Our report underlines the relevance of an early and careful clinical evaluation in neonates with ankyloblefaron, facial dysmorphism, and signs of ectodermal dysplasia. In these cases, the suspicion of AEC syndrome must be promptly raised, and sequencing analysis of TP63 early performed as well. An individualized, multidisciplinary and long-term follow-up should be guaranteed to affected subjects and their families, also to identify associated morbidities and prevent possible serious complications and adverse outcomes.

Autosomal recessive polycystic kidney disease: case report of a newborn with rare PKHD1 mutation, rapid renal enlargement and early fatal outcome.

INTRODUCTION: Autosomal recessive polycystic kidney disease (ARPKD; MIM#263200) is one of the most frequent pediatric renal cystic diseases, with an incidence of 1:20,000. It is caused by mutations of the PKHD1 gene, on chromosome 6p12. The clinical spectrum is highly variable, ranging from late-onset milder forms to severe perinatal manifestations. The management of newborns with severe pulmonary insufficiency is challenging, and causes of early death are sepsis or respiratory failure. In cases of massive renal enlargement, early bilateral nephrectomy and peritoneal dialysis may reduce infant mortality. However, there is no conclusive data on the role of surgery, and decision-making is driven by patient's clinical condition and expertise of the center. PATIENT PRESENTATION: We hereby describe a preterm female newborn with perinatal, rapid and bilateral, abnormal growth of both kidneys, respiratory failure and initial signs of liver disease. She was subsequently confirmed to be affected by a rare and severe homozygous mutation of the PKHD1 gene, inherited from both her consanguineous parents. Our patient died 78 days after birth, due to a fungal sepsis which worsened her respiratory insufficiency. CONCLUSIONS: This patient report shows some of the clinical and ethical issues of neonatal ARPKD, and the need of multidisciplinary approach and good communication with the family. Target next generation sequencing (NGS) techniques may guide and support clinicians, as well as guarantee to these patients the most appropriate clinical management, avoiding unnecessary and/or disproportionate treatments.

Neonatal hyperinsulinemic hypoglycemia: case report of kabuki syndrome due to a novel KMT2D splicing-site mutation.

BACKGROUND: Persistent neonatal hypoglycemia, owing to the possibility of severe neurodevelopmental consequences, is a leading cause of neonatal care admission. Hyperinsulinemic hypoglycemia is often resistant to dextrose infusion and needs rapid diagnosis and treatment. Several congenital conditions, from single gene defects to genetic syndromes should be considered in the diagnostic approach. Kabuki syndrome type 1 (MIM# 147920) and Kabuki syndrome type 2 (MIM# 300867), can be associated with neonatal hyperinsulinemic hypoglycemia. PATIENT PRESENTATION: We report a female Italian (Sicilian) child, born preterm at 35 weeks gestation, with persistent hypoglycemia. Peculiar facial dysmorphisms, neonatal hypotonia, and cerebellar vermis hypoplasia raised suspicion of Kabuki syndrome. Hyperinsulinemic hypoglycemia was confirmed with glucagon test and whole-exome sequencing (WES) found a novel heterozygous splicing-site mutation (c.674-1G > A) in KMT2D gene. Hyperinsulinemic hypoglycemia was successfully treated with diazoxide. At 3 months corrected age for prematurity, a mild global neurodevelopmental delay, postnatal weight and occipitofrontal circumference growth failure were reported. CONCLUSIONS: Kabuki syndrome should be considered when facing neonatal persistent hypoglycemia. Diazoxide may help to improve hyperinsulinemic hypoglycemia. A multidisciplinary and individualized follow-up should be carried out for early diagnosis and treatment of severe pathological associated conditions.

Total colonic aganglionosis and cleft palate in a newborn with Janus-cysteine 618 mutation of RET proto-oncogene: a case report.

BACKGROUND: Hirschsprung disease, the most important congenital colonic dysmotility in children results from neural crest migration, differentiation, proliferation, or apoptosis defects where the rearranged during transfection (RET)-Protooncogene pathway has a central role. Although palatal and retinal anomalies in the context of chromosomopathies and some mono-/oligogenic syndromes are reported associated with Hirschsprung disease the role of inactivating RET mutations in these cases is not clarified. CASE PRESENTATION: We report on a dysmorphic newborn with cleft palate and palatal synechia, who showed intestinal obstruction after 24 h of life. Transient ileostomy and surgical biopsies were performed to diagnose aganglionosis of the colon and last ileal loop. No chromosomal anomalies or copy number variations were found. We identified a paternal heterozygous germline mutation c.1852 T > C, which results in the substitution of cysteine by arginine in the RET-receptor tyrosine kinase (p.C618R mutation). There was no family history of Hirschsprung disease, but the father underwent surgery for medullary thyroid carcinoma and was affected by retinal dystrophy. CONCLUSIONS: The occurrence of Hirschsprung disease and carcinoma shows how a single mutation may be responsible for adverse effects: gain and loss of function of the same receptor. Furthermore, it would be interesting to study its dual role in face and retina embryology, and to extend targeted investigations of RET hotspots in these developmental abnormalities to facilitate counselling, follow-up, and tumor prevention. Complex surgical procedures and genetic testing as well as socio-economic impact are a challenge for familiar compliance.

Novel LRPPRC compound heterozygous mutation in a child with early-onset Leigh syndrome French-Canadian type: case report of an Italian patient.

BACKGROUND: Mitochondrial diseases, also known as oxidative phosphorylation (OXPHOS) disorders, with a prevalence rate of 1:5000, are the most frequent inherited metabolic diseases. Leigh Syndrome French Canadian type (LSFC), is caused by mutations in the nuclear gene (2p16) leucine-rich pentatricopeptide repeat-containing (LRPPRC). It is an autosomal recessive neurogenetic OXPHOS disorder, phenotypically distinct from other types of Leigh syndrome, with a carrier frequency up to 1:23 and an incidence of 1:2063 in the Saguenay-Lac-St Jean region of Quebec. Recently, LSFC has also been reported outside the French-Canadian population. PATIENT PRESENTATION: We report a male Italian (Sicilian) child, born preterm at 28 + 6/7 weeks gestation, carrying a novel LRPPRC compound heterozygous mutation, with facial dysmorphisms, neonatal hypotonia, non-epileptic paroxysmal motor phenomena, and absent sucking-swallowing-breathing coordination requiring, at 4.5 months, a percutaneous endoscopic gastrostomy tube placement. At 5 months brain Magnetic Resonance Imaging showed diffuse cortical atrophy, hypoplasia of corpus callosum, cerebellar vermis hypoplasia, and unfolded hippocampi. Both auditory and visual evoked potentials were pathological. In the following months Video EEG confirmed the persistence of sporadic non epileptic motor phenomena. No episode of metabolic decompensation, acidosis or ketosis, frequently observed in LSFC has been reported. Actually, aged 14 months corrected age for prematurity, the child shows a severe global developmental delay. Metabolic investigations and array Comparative Genomic Hybridization (aCGH) results were normal. Whole-exome sequencing (WES) found a compound heterozygous mutation in the LRPPRC gene, c.1921-7A > G and c.2056A > G (p.Ile686Val), splicing-site and missense variants, inherited from the mother and the father, respectively. CONCLUSIONS: We first characterized the clinical and molecular features of a novel LRPPRC variant in a male Sicilian child with early onset encephalopathy and psychomotor impairment. Our patient showed a phenotype characterized by a severe neurodevelopmental delay and absence of metabolic decompensation attributable to a probable residual enzymatic activity. LRPPRC is a rare cause of metabolic encephalopathy outside of Québec. Our patient adds to and broaden the spectrum of LSFC phenotypes. WES analysis is a pivotal genetic test and should be performed in infants and children with hypotonia and developmental delay in whom metabolic investigations and aCGH are normal.

Neonatal ten-year retrospective study on neural tube defects in a second level University Hospital.

BACKGROUND: Aim of this retrospective study was to describe clinical characteristics, diagnostic work-up, management and follow-up of newborns with neural tube defects (NTDs), admitted to the Mother and Child Department of the University Hospital of Palermo, in a ten years period. METHODS: The medical records of 7 newborns (5 males and 2 females) admitted, over a 10-year period from January 2010 to March 2020, to our Department on the first day of life were reviewed. Analyzed data were related to familiar and/or maternal risk factors (consanguinity, maternal preexisting and/or gestational diseases, exposure to teratogen/infectious agents, lack of preconception folic acid supplement), demographic (ethnicity/origin, residence) and clinical features (eventual use of assisted reproduction techniques, prenatal diagnosis, gestational age, fetal presentation, type of delivery, birth weight, preoperative imaging, antibiotics and analgesics use, description of the surgery intervention, length of hospital stay, comorbidities, complications), and follow-up. RESULTS: In our sample we observed a wide spectrum of NTDs: 3 newborns had open NTDs, namely myelomeningocele (2 lumbosacral, one of which associated with extradural lipoma, and 1 sacral), and 4 closed ones, including 2 with meningocele (occipital), 1 filar lipoma associated with dermal sinus, and 1 terminal myelocystocele. Our patients were discharged between 8 and 22 days of life. The neurodevelopmental follow-up showed a favorable outcome for 4 of the 7 patients, and the appearance over time of neurological impairment (motor and/or autonomic) in the newborns with open NTDs. CONCLUSIONS: This study describes familiar and/or maternal risk factors and demographic and clinical features of a single-center series of newborns with NTDs. It may provide a further outline of the actual phenotypic spectrum of these malformations, and new insights into epidemiological aspects and comprehensive management of the patients, including diagnostic work-up and follow-up evaluations.

Recognizable neonatal clinical features of aplasia cutis congenita.

BACKGROUND: Aplasia cutis congenita (ACC), classified in nine groups, is likely to be underreported, since milder isolated lesions in wellbeing newborns could often be undetected, and solitary lesions in the context of polymalformative syndromes could not always be reported. Regardless of form and cause, therapeutic options have in common the aim to restore the deficient mechanical and immunological cutaneous protection and to limit the risk of fluid leakage or rupture of the exposed organs. We aimed to review our institutional prevalence, comorbidities, treatment and outcome of newborns with ACC. METHODS: We conducted a retrospective study including all newborns affected by ACC and admitted at the University Mother-Child Department from October 2010 to October 2019. Anthropometric and clinical characteristics of ACC1 versus a non-isolated ACC group were analyzed. RESULTS: We encountered 37 newborns, 16 with ACC1 versus 21 with non-isolated ACC. The incidence rate of 0.1% in ACC1 was higher than expected, while 19% of cases showed intrafamilial autosomal dominant transmission. Higher birth weight centile, though lower than reference population, being adequate for gestational age, normal Apgar score and euglycemia characterizing ACC1 resulted associated to a rapid tissue regeneration. Non-isolated ACC, in relation to concomitant congenital anomalies and higher prematurity rate, showed more surgical and medical complications along with the risk of neonatal death. Specifically, newborns with ACC4 were characterized by the frequent necessity of abdominal wall defect repair, responsible for the occurrence of an abdominal compartment syndrome. CONCLUSION: Prompt carefully assessment of the newborn with ACC in order to exclude concomitant other congenital malformations, provides clues to the underlying pathophysiology, and to the short-term prognosis. Family should be oriented toward identification of other family members affected by similar pathology, while obstetric history should exclude initial multiple pregnancy with death of a co-twin, placental anomalies and drug assumption. Molecular-genetic diagnosis and genetic counseling are integrative in individualized disease approach.

NF1 microdeletion syndrome: case report of two new patients.

BACKGROUND: 17q11.2 microdeletions, which include the neurofibromatosis type 1 (NF1) gene region, are responsible for the NF1 microdeletion syndrome, observed in 4.2% of all NF1 patients. Large deletions of the NF1 gene and its flanking regions are associated with a more severe NF1 phenotype than the NF1 general population. CASE PRESENTATION: We hereby describe the clinical and molecular features of two girls (aged 2 and 4 years, respectively), with non-mosaic atypical deletions. Patient 1 showed fifteen café-au-lait spots and axillary freckling, as well as a Lisch nodule in the left eye, strabismus, high-arched palate, malocclusion, severe kyphoscoliosis, bilateral calcaneovalgus foot, mild generalized hypotonia, hyperactivity and deficits of speech-related abilities. NF1 genomic rearrangements through multiplex ligation-dependent probe amplification (MLPA) detected an heterozygous deletion of the whole NF1 gene. Array comparative genomic hybridization (a-CGH) analysis defined a 17q11.2 deletion of about 1 Mb (breakpoints at positions 29,124,299 and 30,151,654), which involved different genes (partially CRLF3, ATAD5, TEFM, ADAP2, RNF135, OMG, EVI2B, EVI2A, RAB11FIP4), including NF1. Patient 2 showed growth and developmental delay, supravalvular pulmonary stenosis, twenty-five café-au-lait spots, axillary freckling, craniofacial dysmorphic features, short neck with pterygium, limb abnormalities and foci of neural dysplasia on brain magnetic resonance imaging (MRI). MLPA detected an heterozygous deletion of NF1, which was detailed by a-CGH indicating the positions 29,124,299 and 30,326,958 as its breakpoints, and which included aside from the genes deleted in Patient 1 also COPRS, UTP6 and partially SUZ12. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletions in both cases. CONCLUSIONS: The present report will likely provide further insights and a better characterization of NF1 microdeletion syndrome.

Clinical and molecular characterization of 112 single-center patients with Neurofibromatosis type 1.

BACKGROUND: The aim of this retrospective study was to define clinical and molecular characteristics of a large sample of neurofibromatosis type 1 (NF1) patients, as well as to evaluate mutational spectrum and genotype-phenotype correlation. NF1 is a relatively common neurogenetic disorder (1:2500-1:3000 individuals). It is caused by mutations of the NF1 gene on chromosome 17ql1.2, with autosomal dominant pattern of inheritance and wide phenotypical variability. Café-au-lait spots (CALs), cutaneous and/or subcutaneous neurofibromas (CNFs/SCNFs), skinfold freckling, skeletal abnormalities, Lisch nodules of the iris and increased risk of learning and intellectual disabilities, as well as tumors of the nervous system and other organs are its main clinical features. METHODS: The preliminary group collected 168 subjects with clinical suspicion of NF1. They were evaluated following the National Institutes of Health (NIH) criteria for NF1, revised by Gutmann et al. 1997, integrated for 67 of them by molecular testing. According to these references, 112 of 168 patients were diagnosed as NF1. The sample was characterized by an equal sex ratio (57 males, 55 females) and age distribution ranging from 10 days to 60 years of age (mean age, 13 years). RESULTS: A wide spectrum of clinical features has been observed in our patients. Mutational analysis resulted positive in 51 cases (76%). Twenty-four mutations detected in our cohort have not been reported to date. CONCLUSIONS: This study may contribute to a better definition of genotypic and phenotypic features of NF1 patients, with respect to further insights into the clinical characterization of the disease. In addition, an amplification of the spectrum of mutations in the NF1 gene has been documented.

A Case of Cardiomyopathy Due to Premature Ductus Arteriosus Closure: The Flip Side of Paracetamol.

Paracetamol (acetaminophen or N-acetyl-p-aminophenol) is considered a safe analgesic and antipyretic nonsteroidal antiinflammatory drug commonly used during pediatric ages and during pregnancy. We report on a term neonate with closed ductus arteriosus, severe cardiomyopathy, right ventricular dysfunction, and functional stenosis of pulmonary arteries at birth after maternal self-medication with paracetamol and consumption of polyphenol-rich foods in late pregnancy. This drug, especially when associated with other vasoconstrictors (such as polyphenols), interferes with prostaglandin metabolism, which seriously accentuates the intrauterine ductus arteriosus constriction and leads to pharmacologic adverse events. We suggest maternal educational programs to avoid risky self-medications and provide training for the best diets.

Dilated azygos arch mimicking an aortic arch anomaly during thoracic surgery.

Cardiovascular malformations are frequently associated in patients with esophageal atresia (EA). We observed azygos continuation mimicking an aortic arch anomaly in four newborns with type III EA. They presented concomitant rib anomalies indicating a common developmental defect. Foreknowledge is important for planning thoracotomy or interventional cardiac catheterization in this population.

Congenital heart defects in newborns with apparently isolated single gastrointestinal malformation: A retrospective study.

BACKGROUND: Congenital gastrointestinal system malformations/abdominal wall defects (GISM) may appear as isolated defects (single or complex), or in association with multiple malformations. The high incidence of association of GISM and congenital heart defects (CHD) in patients with syndromes and malformative sequences is known, but less expected is the association of apparently isolated single GISM and CHD. The aim of this study was to investigate the frequency of CHD in newborns with isolated GISM, and the possibility to modify the diagnostic-therapeutic approach just before the onset of cardiac symptoms or complications. METHODS: Anamnestic, clinical, and imaging data of newborns requiring abdominal surgery for GISM, between 2009 and 2014, were compared with a control group of healthy newborns. Distribution of GISM and cardiovascular abnormalities were analyzed, and risk factors for adverse outcomes were identified. RESULTS: Seventy-one newborns with isolated GISM were included in this study. More frequent GISM were intestinal rotation and fixation disorders. CHD were observed in 15.5% of patients, augmenting their risk for morbidity. Risk factors for morbidity related to sepsis were identified in central venous catheter, intestinal stoma, and H2-inhibitor-drugs. Moreover, 28.2% of newborns presented only functional cardiac disorders but an unexpectedly higher mortality. CONCLUSIONS: The high incidence of congenital heart disease in infants with apparently isolated GISM confirms the need to perform an echocardiographic study before surgery to improve perioperative management and prevent complications such as sepsis and endocarditis.