Gingivosupraperiosteoplasty following Presurgical Maxillary Orthopedics Is Associated with Normal Midface Growth in Complete Unilateral and Bilateral Cleft Patients at Mixed Dentition.

BACKGROUND: Passive orthodontic appliances and gingivosupraperiosteoplasty are adjuncts that can be used by surgeons at the time of primary cleft lip repair. These treatments, along with the surgical technique of cleft lip and palate repair, may impact midface growth. The objective of this study was to describe the authors' protocol for unilateral and bilateral cleft lip repair and to evaluate midfacial growth in a cohort of patients at mixed dentition who had undergone presurgical passive orthodontic appliance therapy and gingivosupraperiosteoplasty at the time of unilateral and bilateral cleft lip repair. METHODS: Fifteen complete unilateral and 15 complete bilateral cleft lip and palate patients underwent passive orthodontic appliance treatment and primary lip repair with gingivosupraperiosteoplasty. Lateral cephalograms were analyzed by three blinded reviewers. Mean cephalometric measurements at mixed dentition were compared to cephalometric values for noncleft patients, unilateral cleft lip and palate patients who did not undergo gingivoperiosteoplasty or presurgical treatment, and unilateral cleft lip and palate patients who underwent gingivoperiosteoplasty/nasoalveolar molding with independent samples t tests. RESULTS: Mean cephalometric values were within age-specific normal values for sella-nasion-A point, sella-nasion-B point, A point-nasion-B point, and facial axis. Eighty-seven (13/15) percent of unilateral cleft lip and palate patients and 93 percent (14/15) of bilateral cleft lip and palate patients did not exhibit skeletal class III malocclusion. There was no significant difference between cephalometric values for our patients and patients who did not receive gingivosupraperiosteoplasty or presurgical treatment or who underwent the gingivoperiosteoplasty/nasoalveolar molding protocol. CONCLUSIONS: Presurgical passive orthodontic appliances, combined with gingivosupraperiosteoplasty at the time of lip repair, leads to normal maxillary development in most patients at mixed dentition. Assessment of midface growth at skeletal maturity is required. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach in a Hispanic Pediatric Patient With APC Gene Variant c.-191T>G.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare gastric polyposis syndrome defined by numerous polyps (>100) in the fundus and body of the stomach with sparing of the lesser curvature and antrum. GAPPS is linked to a variant in the promoter 1B region of the APC gene. These variants carry a high risk of developing gastric adenocarcinoma, which can occur at an early age. We report a case of GAPPS discovered in a 16-year-old Hispanic girl after endoscopy detected extensive fundic gland polyposis. Genetic testing revealed a promoter 1B point mutation of the APC gene, variant c.-191T>G. Although similar variants have been reported (i.e., c.-191T>C, c.-195A>C, c.-192A>G) in association with GAPPS, variant c.-191T>G has not nor has GAPPS ever been described in a Hispanic individual before.

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome.

Raine syndrome is a rare, autosomal recessive, osteosclerotic bone dysplasia due to pathogenic variants in FAM20C. The clinical phenotype is characterized by generalized osteosclerosis affecting all bones, cerebral calcifications, and craniofacial dysmorphism. Most cases present during the neonatal period with early lethality due to pulmonary hypoplasia and respiratory compromise while only few affected individuals have been reported to survive into adulthood. FAM20C is a ubiquitously expressed protein kinase that contains five functional domains including a catalytic domain, a binding pocket for FAM20A and three distinct N-glycosylation sites. We report a newborn infant with a history of prenatal onset fractures, generalized osteosclerosis, and craniofacial dysmorphism and early lethality. The clinical presentation was highly suggestive of Raine syndrome. A homozygous, novel missense variant in exon 5 of FAM20C (c.1007T>G; p.Met336Arg) was identified by targeted Sanger sequencing. Following in silico analysis and mapping of the variant on a three-dimensional (3D) model of FAM20C it is predicted to be deleterious and to affect N-glycosylation, protein folding, and subsequent secretion of FAM20C. In addition, we reviewed all published FAM20C mutations and observed that most pathogenic variants affect functional regions within the protein establishing evidence for an emerging genotype-phenotype correlation.

Revascularization After Intravitreal Bevacizumab and Laser Therapy of Bilateral Retinal Vascular Occlusions in Incontinentia Pigmenti (Bloch-Sulzberger Syndrome).

No consensus exists for the treatment of retinopathy in incontinentia pigmenti (IP). Vascular ischemia leads to tractional retinal detachments if untreated. Ultra-widefield fluorescein angiography (FA) is used to follow the vascular status of the retina. A 13-week-old female with IP presented with bilateral retinal vascular occlusions in both eyes. Ultra-widefield FA showed reperfusion after treatment with intravitreal bevacizumab (IVB) and angiography-guided laser to the avascular retina. Anti-vascular endothelial growth factor treatment reduces neovascularization and allows for growth of retinal vessels. IVB and FA-guided laser to the avascular retina is an option in IP. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e33-e37.].

Ophthalmic findings in Frank-ter Haar syndrome: report of a sibling pair.

Frank-ter Haar syndrome (FTHS) is an autosomal recessive disorder characterized by abnormalities that affect the development of bone, heart, and eyes. We report a sibling pair with FTHS caused by a homozygous, novel mutation pLys133Glnfs*13 in the SH3PXD2B gene: one sibling had bilateral ocular hypertension and unilateral colobomas of iris, choroid and retina; the other, unilateral myelinated nerve fiber layer of the optic disk and papilledema due to idiopathic intracranial hypertension. Both children had refractive amblyopia and megalocornea.

New JAG1 Mutation Causing Alagille Syndrome Presenting With Severe Hypercholesterolemia: Case Report With Emphasis on Genetics and Lipid Abnormalities.

Context: Alagille syndrome is a rare autosomal-dominant genetic disorder caused by defects in the Notch signaling pathway, which involves multiple organ systems. Bile duct paucity is the main characteristic feature of the disease, which often leads to cholestatic hypercholesterolemia. Case Description: We report the case of a male infant who had developed failure to thrive, jaundice, intermittent pruritus, and multiple diffuse symmetrical skin xanthomas at 1 year of age. He was diagnosed with pulmonary stenosis, butterfly vertebrae of T4, T6, and T8; horseshoe kidney, and embryotoxon in the left eye. Laboratory workup revealed severe hypercholesterolemia. Alagille syndrome was suspected and confirmed by genetic testing, which identified a previously undescribed frameshift pathogenic heterozygous variant in the JAG1 gene, p.Arg486Lysfs*5. Conclusions: Here, we report a unique case of a patient diagnosed with Alagille syndrome who was found to have a previously undescribed frameshift pathogenic mutation in the JAG1 gene and who presented with xanthomatosis and levels of hypercholesterolemia more than 2 times higher than those previously reported in the literature. We also provide a review of the different pathophysiologic mechanisms associated with the increase in serum cholesterol and low-density lipoprotein cholesterol concentrations seen in cholestatic liver disease in general and in Alagille syndrome in particular.

Neonatal diagnosis of a patient with hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome associated with cerebral infarction.

Hypoparathyroidism, sensorineural deafness and renal dysplasia syndrome (HDRS) is comprised of a triad of conditions. It is an autosomal dominant condition caused by mutations in the GATA3 gene, located at 10p15, a critical region in the development of the embryonic parathyroid glands, inner ear, and kidneys. Here we describe the case of a patient with all three components of HDR syndrome diagnosed in the neonatal period who presented with cerebral infarction, hypocalcemia, and renal anomalies. Upon chromosomal microarray he was found to have an interstitial deletion at 10p, which produced a partial deletion in the GATA3 gene.

Genotype-phenotype analysis of the branchio-oculo-facial syndrome.

Branchio-oculo-facial syndrome (BOFS; OMIM#113620) is a rare autosomal dominant craniofacial disorder with variable expression. Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. Having determined that mutations involving TFAP2A result in BOFS, we studied a total of 30 families (41 affected individuals); 26/30 (87%) fulfilled our cardinal diagnostic criteria. The original family with the 3.2 Mb deletion including the TFAP2A gene remains the only BOFS family without the typical CL/P and the only family with a deletion. We have identified a hotspot region in the highly conserved exons 4 and 5 of TFAP2A that harbors missense mutations in 27/30 (90%) families. Several of these mutations are recurrent. Mosaicism was detected in one family. To date, genetic heterogeneity has not been observed. Although the cardinal criteria for BOFS have been based on the presence of each of the core defects, an affected family member or thymic remnant, we documented TFAP2A mutations in three (10%) probands in our series without a classic cervical cutaneous defect or ectopic thymus. Temporal bone anomalies were identified in 3/5 patients investigated. The occurrence of CL/P, premature graying, coloboma, heterochromia irides, and ectopic thymus, are evidence for BOFS as a neurocristopathy. Intrafamilial clinical variability can be marked. Although there does not appear to be mutation-specific genotype-phenotype correlations at this time, more patients need to be studied. Clinical testing for TFAP2A mutations is now available and will assist geneticists in confirming the typical cases or excluding the diagnosis in atypical cases.

Phenotype and natural history in Marshall-Smith syndrome.

Marshall-Smith syndrome (MSS) is a distinctive entity of unknown etiology with fewer than 50 patients described in the medical literature to date. Through an International collaboration and use of an online wiki to facilitate data collection and sharing, we further delineate the phenotype and natural history of this syndrome. We present 15 new patients, the oldest being 30 years, provide an update on four previously published cases, and compare all patients with other patients reported in literature. Main clinical features are moderate to severe developmental delay with absent or limited speech, unusual behavior, dysharmonic bone maturation, respiratory compromise secondary to upper airway obstruction, short stature, and kyphoscoliosis. Facial features are characteristic with high forehead, underdeveloped midface, proptosis, anteverted nares, and everted lips. Minor abnormalities of brain morphology such as hypoplasia of the corpus callosum are common. Mortality from respiratory complications is high, but airway support increasingly allows survival into adulthood. Array-CGH was performed on 12 of the cohort and no copy number variants of clear clinical relevance were identified. The present study is the first reported use of an online wiki to aid delineation of a genetic syndrome, and illustrates its value in collecting detailed data in rare conditions.

Epiretinal membranes indicate a severe phenotype of neurofibromatosis type 2.

PURPOSE: The purpose of this study was to describe a subset of severely affected patients with neurofibromatosis type 2 (NF2), multiple central nervous system tumors, and characteristic retinal lesions. METHODS: This is a retrospective observational case series of 4 patients with NF2. The time domain-optical coherence tomography findings of three patients have previously been described in another series. RESULTS: Ophthalmic signs were identified at a mean age of 6 years, and NF2 was diagnosed at a mean age of 11 years. Patients presented with diminished visual acuity in one or both eyes and epiretinal membranes in the absence of posterior vitreous detachment. The biomicroscopic and optical coherence tomography features were distinct from secondary epiretinal membranes or combined hamartomas of the retina and retinal pigment epithelium and pathognomonic for NF2. The ophthalmic manifestations were recognized before neurologic signs and led to the diagnosis of NF2 in 3 of the 4 patients. Each patient had > or =2 central nervous system tumors at the time of diagnosis, and 3 of 4 eventually required neurosurgical interventions for symptomatic, compressive lesions at a mean age of 12 years. CONCLUSION: Recognition of epiretinal membranes with a characteristic optical coherence tomography appearance may permit early diagnosis in neurologically asymptomatic children with a severe phenotype of NF2.

Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis.