Fetal early motor neuron disruption and prenatal molecular diagnosis in a severe BICD2-opathy.

BICD2 (BICD Cargo Adaptor 2, MIM*609797) mutations are associated with severe prenatal-onset forms of spinal muscular atrophy, lower extremity-predominant 2B (SMALED2B MIM 618291) or milder forms with childhood-onset (SMALED2A MIM 615290). Etiopathogenesis is not fully clarified and a wide spectrum of phenotypic presentations is reported, ranging from extreme prenatal forms with adverse outcome, to slow progressive late-onset forms. We report a fetus at 22 gestational weeks with evidence of Arthrogryposis Multiplex Congenita on ultrasound, presenting with fixed extended lower limbs and flexed upper limbs, bilateral clubfoot and absent fetal movements. A trio-based prenatal Exome Sequencing was performed, disclosing a de novo heterozygous pathogenic in frame deletion (NM_015250.3: c.1636_1638delAAT; p.Asn546del) in BICD2. After pregnancy termination, quantitative analysis on NeuN immunostained spinal cord sections of the ventral horns, revealed that neuronal density was markedly reduced compared to the one of an age-matched normal fetus and an age-matched type-I Spinal Muscular Atrophy sample, used as a comparative model. The present case, the first prenatally diagnosed and neuropathologically characterized, showed an early motor neuron loss in SMALED2B, providing further insight into the pathological basis of BICD2-opathies.

A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1.

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2) is a rare autosomal recessive neuromuscular disorder characterized by arthrogryposis multiplex congenita and prenatal fractures of the long bones, with poor prognosis. The most affected patients present with biallelic loss-of-function nucleotide variants in ASCC1 gene, coding a subunit of the transcriptional coactivator ASC-1 complex, although the exact pathogenesis is yet unknown. This work describes the first case of SMABF2 in a stillbirth with documented evolution of the disease in the prenatal period. A microdeletion copy number variant (CNV) of about 64 Kb, involving four exons of ASCC1, was firstly detected by microarray analysis, requested for arthrogryposis and hydrops. Subsequent exome analysis disclosed a nucleotide variant of the same gene [c.1027C>T; (p. Arg343*)], resulting in the introduction of a premature termination codon. This stillbirth represents the first case of ASCC1 compound heterozygosity, due to an exonic microdeletion and a nucleotide variant, expanding the mutational spectrum of this gene. It also provides further evidence that exonic CNVs are an underestimated cause of disease-alleles and that the integrated use of the last generation genetic analysis tools, together with careful clinical evaluations, are fundamental for the characterization of rare diseases even in the prenatal setting.

A Systematic Review of NAFLD-Associated Extrahepatic Disorders in Youths.

BACKGROUND: There is growing evidence that non-alcoholic fatty liver disease (NAFLD) is a disease affecting not only the liver but also extrahepatic organs. AIM: To investigate whether in youths NAFLD is associated with extrahepatic complications such as subclinical atherosclerosis, cardiac abnormalities, hypertension, type 2 diabetes, decreased bone mineral density, renal dysfunction, obstructive sleep apnea, and polycystic ovary syndrome. METHODS: We systematically reviewed PubMed; Scopus; Embase; and the Cochrane Library databases up to 28 February 2019 and assessed the quality of studies using the Newcastle-Ottawa Scale. RESULTS: Thirty-five articles were selected for this systematic review: fifteen (4627 participants) evaluated the association of NAFLD with subclinical atherosclerosis; four (969 participants) with cardiac abnormalities; two (550 participants) with hypertension; four (1328 participants) with diabetes; six (523 participants) with low bone mineral density; two (865 participants) with renal dysfunction; one with obstructive sleep apnea; and one with polycystic ovary syndrome. Most studies found that youths with NAFLD have increased features of subclinical atherosclerosis; as well as of cardiac alterations. Limited data were available to endorse a solid estimate of the prevalence of diabetes; low mineral density and renal dysfunction in the pediatric NAFLD population. CONCLUSION: NAFLD-related intermediate CVD outcomes can occur and be detected early in young populations.

Cutis tricolor: a literature review and report of five new cases.

BACKGROUND: Cutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far either: (I) as an purely cutaneous trait; (II) as a part of a complex malformation phenotype (Ruggieri-Happle syndrome, RHS) including distinct facial features, eye (cataract), skeletal (skull and vertebral defects, and long bones dysplasia), nervous system (corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly) and systemic abnormalities; (III) as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata); and (IV) in association with other skin disturbances [e.g., cutis marmorata telangectasica congenita (phacomatosis achromico-melano-marmorata)] or in the context of other skin (e.g., ataxia-telangiectasia and phacomatosis pigmentovascularis, PPV) or complex malformation phenotypes (e.g., microcephaly and dwarfism). METHODS: (I) Review of the existing literature; and (II) information on our personal experience (clinical, laboratory and imaging data) on new cases with cutis tricolor seen and followed-up at our institutions during years 2010-2016. RESULTS: The existing literature revealed 19 previous studies (35 cases) with pure cutaneous or syndromic cutis tricolor phenomena. Our personal experience included 5 unpublished patients (3 boys; 2 girls; currently aged 2 to 14 years) seen and followed-up at our Institutions in Italy who had: (I) skin manifestations of the cutis tricolor type (N=5); (II) skeletal abnormalities including small skull (n=2), obtuse angle of mandible (n=3), mild to moderate scoliosis (n=3), vertebral defects (n=3), and long bones bowing (n=3); mild psychomotor delay (n=3); epilepsy (n=2); anomalies of the corpus callosum (n=3); and cavum vergae (n =2). CONCLUSIONS: This study further confirms and expands the overall phenotype of cutis tricolor. By literature review and personal experience we conclude that the skin abnormalities of the cutis tricolor type are stable over time; the skeletal defects are mild to moderate and do not progress or cause relevant orthopaedic complications; the neurological/behavioural phenotype does not progress and the paroxysmal events (when present) tend to decrease over time; there is a typical facial phenotype in some patients (long, elongated face, thick and brushy eyebrows, hypertelorism, deep nasal bridge with large bulbous nose and anteverted nostrils), which characterizes a somewhat distinct syndromic phenotype; some patients may develop early onset cataracts. The allelic dydymotic hypothesis of post-zygotic mutations likely involving the same gene loci could well explain the overall skin, bone, lens and nervous system phenomena of migration of different streaks of clones in the different tissues.

Recurrent pyriform sinus fistula successfully treated by endoscopic Glubran 2 sealing: A rare case and literature review.

OBJECTIVES: The authors present the case of a 3-year-old girl with a history of complicated surgery for removing a third branchial cleft fistula. METHODS: An endoscopic approach using N-butyl-2-acrylate and metacrilosisolfolane glue (GLUBRAN 2) to seal the fistula was performed. RESULTS: The clinical and radiological 6-year follow-up confirmed the absence of the fistulous orifice and the persistence of scar due to previous open-neck surgical procedures. CONCLUSION: endoscopic Glubran 2 sealing has been an effective treatment procedure for branchial fistula.

The use of piezosurgery in cranial surgery in children.

Piezosurgery is an alternative surgical technique, now widely tested, that uses ultrasounds for bone cutting. This device uses ultrasounds to section hard tissues without harming surrounding soft tissues. The authors analyzed their experience in craniomaxillofacial procedures with piezosurgery. A comparison between operation timing and complication rates between piezosurgery and traditional cutting instruments has been performed. A total of 27 patients were examined (15 females and 12 males; average age, of 5.5 months) affected by craniosynostosis. The aim of this study was to analyze the advantages and disadvantages of piezosurgery in pediatric craniofacial procedures. Piezoelectric device in this study has shown being a valid instrument for bone cutting in accurate procedures, because it allows performing a more precise and safer cutting, without the risk of harming surrounding tissues.

Laparoscopic pyloroplasty for idiopathic non-hypertrophic pyloric stenosis in a child.

Acquired gastric outlet obstruction (GOO) during infancy and childhood represents an uncommon event. We describe a 6-year-old boy with GOO who did not respond to medical treatment or to endoscopic pyloric balloon dilatations. The stenosis was successfully treated with laparoscopic pyloroplasty which relieved the obstruction.

Video: argon plasma coagulator in a 2-month-old child with tracheoesophageal fistula.

A 2 month-old boy was admitted to the authors' hospital because of regurgitation and persistent cough during breastfeeding. A chest X-ray examination and a barium esophagogram disclosed small amounts of barium passing in the trachea, suggesting a tracheoesophageal fistula (TEF). Bronchoscopy combined with upper gastrointestinal (GI) endoscopy performed with the patient under general anesthesia confirmed the fistula. The TEF was treated by injection of 1 ml Glubran 2 from the esophageal side. A nasogastric tube was placed for feedings, and 7 days later, a barium esophagogram showed a reduction of caliber but not complete closure of the TEF. Unsuccessful fistula obliteration with Glubran was attributed to technical difficulties in catheterization of the fistula orifice, mainly resulting from its close proximity to the upper esophageal sphincter and to its small caliber. Therefore, an argon plasma coagulator (APC) probe with a circumferentially oriented nozzle was used from the esophageal side as an alternative technique to fulgurate the residual fistula orifice (see video). A nasogastric tube was placed for feedings. Oral feeding was started 7 days later when a barium esophagogram confirmed complete fistula closure. At the 2-year follow-up visit, the boy was asymptomatic, and the barium esophagogram was negative. This report describes a case in which esophagoscopy gave a clear view of the fistula due to its direction from esophagus to trachea. Complete fistula obliteration was not obtained with Glubran. However, APC was successfully used to close the residual fistula orifice. The authors suggest that APC can be used as an alternative endoscopic technique to repair TEF when other techniques fail.

Complex malformation (Ruggieri-Happle) phenotype with "cutis tricolor" in a 10-year-old girl.

The term cutis tricolor describes the combination of congenital hyper- and hypo-pigmented skin lesions in close proximity to each other in a background of normal complexion. It is currently regarded as a twin-spotting phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far: (a) as an isolated skin manifestation; (b) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome - RHS); (c) as a distinct phenotype [cutis tricolor parvimaculata]; (d) in association with other (e.g., vascular) skin disturbances. We report a novel case of cutis tricolor in a 10-year-old girl who had dysmorphic facial features [alike those seen in cases with syndromic (RHS) cutis tricolor], overall overgrowth [weight, length, and head circumference were >90th percentile; there was increased bone age], mild cognitive delay (current IQ=55), behavioural disturbances, febrile seizures and (later) partial complex epilepsy (currently under good control), and skeletal defects [i.e., posterior scalloping of the lumbar vertebrae]. We discuss the main similarities and differences between the various phenotypes in the spectrum of cutis tricolor and with other conditions sharing features with the present case.

Incidence and predisposing factors for severe disease in previously healthy term infants experiencing their first episode of bronchiolitis.

AIM: To determine the incidence and predisposing factors for severe bronchiolitis in previously healthy term infants <12 months of age experiencing their first episode of bronchiolitis. METHODS: Epidemiological, clinical and virological data were prospectively collected. Severity was assessed by the need for ventilatory support. RESULTS: Of the 310 infants enrolled, 16 (5.1%) presented with severe bronchiolitis requiring ventilatory support (11 since admission). Compared with infants with less severe bronchiolitis, infants with severe disease presented with lower birth weight, gestational age, postnatal weight and postnatal age, and were more likely to be born by cesarian section. C-reactive protein positive results (>0.8 mg/dL) and pulmonary consolidation on chest X-ray were more common among infants with severe disease. Severity was independently associated with younger age on admission <30 days, respiratory syncytial virus (RSV) infection and lymphocyte counts < 3200/µL. No significant differences were found between epidemiologic variables. CONCLUSIONS: Severe bronchiolitis is uncommon in previously healthy term infants <12 months of age and when present develops soon after disease onset. Severity is predicted by young age and RSV carriage, whereas epidemiologic variables seem less likely to intervene.

Spectrum of skeletal abnormalities in a complex malformation syndrome with "cutis tricolor" (Ruggieri-Happle syndrome).

BACKGROUND: The term cutis tricolor describes the combination of congenital hyper- and hypopigmented skin lesions in close proximity to each other in a background of normal complexion. This phenomenon has been reported: (i) as a purely cutaneous trait; (ii) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome - RHS); (iii) as a distinct type [cutis tricolor parvimaculata]; (iv) in association with other (e.g. vascular) skin disturbances. OBJECTIVES: To delineate the spectrum of skeletal defects in cutis tricolor. METHODS: Retrospective and prospective analysis of skeletal surveys in 14 subjects (eight men; six women; aged 2-28 years) with cutis tricolor [4 purely cutaneous trait; 10 syndromic (RHS)]. RESULTS: Bone abnormalities were recorded in 71.4% (10/14) of patients [100% (10/10) of cases with (other-than-skeletal) extra-cutaneous manifestations vs. null (0/4) in cases with purely cutaneous traits] and included overall small skull (n = 6); prognathism (n = 6); 'J'-shaped pituitary fossa (n = 1); absence of atlas posterior arch (n = 3); frontal bossing (n = 6); scoliosis (n = 9) with kyphosis (n = 6) and/or lordosis (n = 6); vertebral (n = 9) and ribs (n = 4) defects. Negative ZFHX1B gene analyses excluded overlaps with Mowat-Wilson syndrome. CONCLUSIONS: Cutis tricolor may be a marker of underlying skeletal involvement particularly in subjects with a complex syndromic (RHS) phenotype.

Three-dimensional magnetic resonance imaging of Kommerell diverticulum in a child with recurrent dysphagia.

We report a case of a 3-year-old girl with a history of recurrent dysphagia and feeding difficulties. After chest x-ray and esophagogram examination, magnetic resonance imaging revealed the presence of a right-sided aortic arch with an aberrant retroesophageal left subclavian artery arising from a Kommerell diverticulum.

Conservative management of cervicomediastinal chyloma in an infant.

The accumulation of chyle into the mediastinum after surgical intervention is considered an extremely rare event, which has been previously described only in adulthood. We report on a 9-month-old boy who developed a cervicomediastinal chyloma after excision of a large left-sided supraclavicular cystic hygroma. Notwithstanding considerable tracheal deviation, the infant remained asymptomatic and was successfully treated by nonoperative treatment. Professionals should be aware of such an unusual condition, which may benefit from expectant management when evaluation establishes a high likelihood of clinical diagnosis, and patient's general condition remains stable. This approach may avoid, with little risk, unnecessary early surgical intervention in some of these patients.

Pigmentary mosaicism, subcortical band heterotopia, and brain cystic lesions.

A 10-year-old boy presented with a severe and diffuse mosaic skin hypopigmentation running (in narrow bands) along the lines of Blaschko associated with mosaic areas of alopecia, facial dysmorphism with midface hypoplasia, bilateral punctate cataract, microretrognathia, short neck, pectus excavatum, joint hypermobility, mild muscular hypotonia, generalized seizures, and mild mental retardation. Cranial magnetic resonance imaging revealed hypoplastic corpus callosum (primarily posterior), subcortical band heterotopia, and diffuse subcortical, periventricular cystic-like lesions. Similar dysmorphic features were observed in the child's mother, but with no imaging abnormalities. The facial phenotype coupled with the cysts in the brain was strongly reminiscent of the oculocerebrorenal Lowe syndrome. Full chromosome studies in the parents and the proband and mutation analysis on peripheral blood lymphocytes (and on skin cultured fibroblasts from affected and unaffected skin areas in the child) in the genes for subcortical band heterotopia (DCX (Xq22.3-q23)], lissencephaly (PAFAH1B1, alias LIS1, at 17p13.3), and oculocerebrorenal syndrome of Lowe (OCRL at Xq23-q24)] were unrevealing. This constellation of multiple congenital anomalies including skin hypopigmentation and eye, musculoskeletal, and nervous system abnormalities was sufficiently characterized to be regarded as a novel example of pigmentary mosaicism of the Ito type (i.e., hypomelanosis of Ito).

VACTERL association and maternal diabetes: a possible causal relationship?

BACKGROUND: Some factors(s)/features(s) of maternal insulin-dependent diabetes mellitus are considered common human teratogens. Although the variable association of cardiac, renal, and skeletal anomalies are commonly observed in infants from diabetic mothers, the relationship between VACTERL (i.e., the association of vertebral and cardiac defects, tracheo-esophageal fistula, renal/radial malformations, and other limb anomalies) and maternal diabetes has not been sufficiently emphasized in the literature. CASE: We report on a 3-year-old boy presenting with a constellation of blastogenetic malformations strongly suggestive of VACTERL association. His mother was affected by insulin-dependent diabetes since she was 7 years old and pregnancy history disclosed very high glucose and HbA1c levels, especially during the first 2 gestational months. CONCLUSIONS: In an attempt to properly counsel the parents, we reviewed the literature and identified four additional patients with VACTERL and first trimester exposure to maternal diabetes mellitus. Although this evidence does not strongly support a causal relationship between these two conditions, additional arguments may substantiate this hypothesis. The pathogenesis of diabetic embryopathy in relation to the VACTERL phenotype is also discussed.

One-stage excision of massive cervicomediastinal lymphangioma in the newborn.

We report the first neonate successfully treated with one-stage complete excision of massive cervicomediastinal lymphangioma producing alarming respiratory distress. Early postoperative course was complicated by refractory bilateral chylothorax, which effectively responded to insertion of external pleuroperitoneal shunts. At the 6-year follow-up, the child remains symptom free and recurrence free. One-stage resection for cervicomediastinal lymphangioma is curative and well tolerated even shortly after birth.

Bilateral periventricular nodular heterotopia with amniotic band syndrome.

The amniotic (constriction) band syndrome is characterized by distal ring constrictions, intrauterine amputations, and acrosyndactyly. External constriction by amniotic bands is the generally accepted mechanism: early amniotic rupture leads to formation of mesodermal fibrous strands that constrict, entangle, and amputate distal portions of limbs. Etiology is heterogeneous. Anecdotal cases involving central nervous system abnormalities (e.g., acrania, anencephaly, polymicrogyria, congenital bilateral perisylvian syndrome, neuronal heterotopia, septo-optic dysplasia, and spinal cord tethering) have been reported. We describe a 9-year-old girl with typical features of constriction band syndrome localized to the lower limbs who had also profound mental retardation and drug-resistant epilepsy associated with bilateral periventricular nodular heterotopia (a brain malformation of neuronal migration and proliferation caused by mutations in the X-linked filamin 1 gene [FLN1] on chromosome Xq28). The karyotype was normal, as was mutational screening for FLN1. The occurrence of bilateral periventricular nodular heterotopia in the context of amniotic band syndrome is novel (chance occurrence of both: 0.000004%).