A 1-Day-Old Girl With Infantile Hemangioma and Sternal Cleft.

CASE PRESENTATION: A newborn girl presented to the hospital on the first day of life because of respiratory failure. She was born at home at 37 weeks' gestation with minimal prenatal care and was found to be small for gestational age. The patient was found to have partial sternal agenesis and sternal cleft, cutis aplasia, left facial hemangioma, micrognathia, wide-spaced nipples, and low-set ears. The mother's and baby's urine toxicology screening were positive for amphetamines. Chest radiographs on admission showed bilateral hazy opacities. CT scan of the chest showed an absent sternum with midline chest wall concavity. The patient was monitored preoperatively in the cardiac ICU for risks of arrythmia, respiratory failure, altered cardiac output, and acute cardiopulmonary decompensation.

Cerebrocostomandibular syndrome: a diagnostic challenge.

A male infant born in a tertiary maternity facility was noted to have microretrognathia, a small mouth and macroglossia at delivery. He was born limp and apnoeic and required multiple attempts at intubation before a definitive airway was eventually sited. Chest X-rays, while in the paediatric intensive care unit, demonstrated dysplastic ribs with associated 'high-riding' clavicles. A later X-ray was reported as showing interrupted posterior ribs. A tracheostomy was formed on day of life 9 given the immediate risk to the baby's airway. Further imaging of the facial bones, skull and brain showed generous CSF spaces over the cerebral convexities and also marked hypoplasia of the mandible and mid-face. The baby's middle ear cavities were shown to be completely opacified. Genetic testing eventually went on to confirm a diagnosis of cerebrocostomandibular syndrome, with the detection of a pathogenic variant of the small nuclear ribonucleoprotein polypeptide B gene.

OHVIRA syndrome: clinical implications of a delayed diagnosis.

Obstructed Hemi Vagina with Ipsilateral Renal Agenesis (OHVIRA) syndrome is a rarely encountered müllerian duct anomaly. Delayed diagnosis is common due to normal onset of puberty and menstruation. We report a case of a woman in her early 20s with a background history of multiple emergency department visits, ward admissions and surgeries for chronic abdominal pain. She was reviewed at 1 month postlaparotomy for recurrent pelvic abscess and was finally diagnosed to have an OHVIRA syndrome, 11 years after her first clinical presentation. Excision of the vaginal septum completely resolved her symptoms. We are reporting this case to highlight the clinical implications resulting from the delayed diagnosis, to look into factors contributing to the delay and to highlight the importance of having a high index of suspicion to diagnose this unique condition.

Joubert syndrome presenting bilateral peroneal neuropathies: A case report.

RATIONALE: Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing. PATIENT CONCERNS AND DIAGNOSIS: A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS. LESSONS: This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.

Diagnostic yield of the chromosomal microarray analysis in turkish patients with unexplained development delay/intellectual disability(ID), autism spectrum disorders and/or multiple congenital anomalies and new clinical findings.

BACKGROUND: Chromosomal microarray analysis is an essential tool for copy number variants detection in patients with unexplained developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The study aims to determine the clinical significance of chromosomal microarray analysis in this patient group. Another crucial aspect is the evaluation of copy number variants detected in terms of the diagnosis of patients. METHODS AND RESULTS: A Chromosomal microarray analysis was was conducted on a total of 1227 patients and phenotype-associated etiological diagnosis was established in 135 patients. Phenotype-associated copy number variants were detected in 11% of patients. Among these, 77 patients 77 (57%, 77/135) were diagnosed with well-recognized genetic syndromes and phenotype-associated copy number variants were found in 58 patients (42.9%, 58/135). The study was designed to collect data of patients in Kocaeli Derince Training and Research Hospital retrospectively. In our study, we examined 135 cases with clinically significant copy number variability among all patients. CONCLUSIONS: In this study, chromosomal microarray analysis revealed pathogenic de novo copy number variants with new clinical features. Chromosomal microarray analysis in the Turkish population has been reported in the largest patient cohort to date.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS): challenges in diagnosis and management.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare, congenital functional intestinal obstruction, characterised by megacystis (bladder distention in the absence of mechanical obstruction), microcolon and intestinal hypoperistalsis (dysmotility).We are reporting a case of a female child with normal antenatal course who presented with recurrent episodes of abdominal distension since the second day of life and underwent negative exploratory laparotomy on multiple occasions. She also had urinary retention with a grossly distended bladder, requiring drainage by clean intermittent catheterisation. Surgical procedures for bowel decompression, including gastrostomy and ileostomy, were carried out without success. Genetic analysis revealed a mutation in the human smooth muscle (enteric) gamma-actin gene (ACTG2 gene), clinching the diagnosis of MMIHS. The patient was managed with parenteral nutrition and prokinetic medications and tolerated jejunostomy feeds for a brief period before she succumbed to the illness.Female neonates or infants presenting with abdominal distension and dilated urinary tract should be investigated for MMIHS early on. A timely diagnosis will enable the early involvement of a multidisciplinary team to provide the best options available for management.

FGD1-related Aarskog-Scott syndrome: Identification of four novel variations and a literature review of clinical and molecular aspects.

Patients with Aarskog-Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype-phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism.   Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: • Aarskog-Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: • We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype-phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function.

Fraser syndrome with limb reduction defect: a rare and unique anatomic variation.

INTRODUCTION: Fraser syndrome, named after George Fraser, is an autosomal recessive disorder showing a highly variable interfamilial phenotypic variation, with malformations ranging from minor symptoms to lethal anomalies like renal agenesis, incompatible with survival. Limb reduction defects have not been reported to be associated with it. CASE PRESENTATION: A 21-year-old primigravida presented to the antenatal outpatient department with a level two targeted anomaly scan report suggestive of severe oligohydramnios with suspected renal agenesis. The cranial vault bones were compressed, and orbital globes and lenses could not be visualized. Renal agenesis was confirmed due to sleeping adrenals sign, non-visualization of the urinary bladder, and Doppler of renal arteries. A detailed examination of the fetal head in the sagittal section showed the absence of an eye globe and lens, arousing suspicion of Fraser syndrome. After pregnancy termination, a complete fetal autopsy was done to look for any additional findings. CONCLUSION: Patients who have a syndromic mix of acrofacial and urogenital abnormalities with or without cryptophthalmos should be evaluated for Fraser syndrome, which can be diagnosed by clinical examination and perinatal autopsy.

Variants in KMT2A in Three Individuals with Previous Suspicion of 22q11.2 Deletion Syndrome.

The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann-Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann-Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses.

Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome.

Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene. The range of clinical manifestations of the ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present two previously unreported paediatric patients with neurodevelopmental challenges, who were diagnosed with missense variants in the ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinaemic hypoglycaemia (HH), a symptom that was not described before in published works. The reason for the occurrence of HH in our proband is not clear, so we try to explain the origin of this symptom in the context of the ZMYND11 syndrome. Thus, this paper contributes to knowledge on the range of possible manifestations of the ZMYND disease and provides further evidence supporting its association with neurodevelopmental challenges.

Goldenhar syndrome with limbal neoformation, microtia and skeletal deformities: a case report and literature review.

BACKGROUND: To report a case of a 4-year-old patient with Goldenhar syndrome. CASE PRESENTATION: The author presents a rare case report involving a 4-year-old boy with multiple malformations. A comprehensive examination showed that the patient primarily had a limbal dermoid. He also has bilateral microtia and ear canal deformities. The skull CT scan and spine X-ray showed Maxillofacial Abnormalities and scoliosis. Whole Exome Sequencing revealed potential gene variations related to microtia. Although certain circumstances prevented us from initiating follow-up treatment for the patient, we have provided a detailed account of the diagnostic methodologies used for this condition. CONCLUSIONS: Goldenhar syndrome is a congenital condition, predominantly presenting as sporadic cases. Its diagnosis and management typically necessitate the involvement of multiple disciplines, including otolaryngology and craniofacial surgery. The syndrome encompasses a variety of craniofacial features, which can facilitate early diagnosis and guide subsequent therapeutic interventions.

Extended phenotypic characterization of a novel Helsmoortel-van der Aa syndrome case series.

The neurodevelopmental disorder known as Helsmoortel-van der Aa syndrome (HVDAS, MIM#616580) or ADNP syndrome (Orphanet, ORPHA:404448) is a multiple congenital anomaly (MCA) condition, reported as a syndrome in 2014, associated with deleterious variants in the ADNP gene (activity-dependent neuroprotective protein; MIM*611386) in several children. First reported in the turn of the century, ADNP is a protein with crucial functions for the normal development of the central nervous system and with pleiotropic effects, explaining the multisystemic character of the syndrome. Affected individuals present with striking facial dysmorphic features and variable congenital defects. Herein, we describe a novel case series of HVDAS Italian patients, illustrating their clinical findings and the related genotype-phenotype correlations. Interestingly, the cutaneous manifestations are also extensively expanded, giving an important contribution to the clinical characterization of the condition, and highlighting the relation between skin abnormalities and ADNP defects.

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

Macular dystrophy in Kabuki syndrome due to de novo KMT2D variants: refining the phenotype with multimodal imaging and follow-up over 10 years: insight into pathophysiology.

BACKGROUND: Kabuki Syndrome is a rare and genetically heterogenous condition with both ophthalmic and systemic complications and typical facial features. We detail the macular phenotype in two unrelated patients with Kabuki syndrome due to de novo nonsense variants in KMT2D, one novel. A follow-up of 10 years is reported. Pathogenicity of both de novo nonsense variants is analyzed. METHODS: Four eyes of two young patients were studied by full clinical examination, kinetic perimetry, short wavelength autofluorescence, full field (ff) ERGs, and spectral-domain optical coherence tomography (SD-OCT). One patient had adaptive optic (AO) imaging. Whole exome sequencing was performed in both patients. RESULTS: Both patients had de novo nonsense variants in KMTD2. One patient had c.14843C>G; p. (Ser4948ter) novel variant and the second c.11119C>T; p. (Arg3707ter). Both had a stable Snellen visual acuity of 0.2-0.3. The retinal multimodal imaging demonstrated abnormalities at the fovea in both eyes: hyperreflectivity to blue light and a well-delimited gap-disruption of ellipsoid and interdigitation layer on OCT. The dark area on AO imaging is presumed to be absent for, or with structural change to photoreceptors. The ff ERGs and kinetic visual fields were normal. The foveal findings remained stable over several years. CONCLUSION: Kabuki syndrome-related maculopathy is a distinct loss of photoreceptors at the fovea as shown by multimodal imaging including, for the first time, AO imaging. This report adds to the literature of only one case with maculopathy with two additional macular dystrophies in patients with Kabuki syndrome. Although underestimated, these cases further raise awareness of the potential impact of retinal manifestations of Kabuki syndrome not only among ophthalmologists but also other healthcare professionals involved in the care of patients with this multisystem disorder.

ARID2, a milder cause of Coffin-Siris Syndrome? Broadening the phenotype with 17 additional individuals.

Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex, including ARID1B, ARID1A, ARID2, SMARCA4, SMARCE1, SMARCB1, SOX11, SMARCC2, DPF2, and more recently, BICRA. Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. The classic finding of fifth digit hypo- or aplasia is seen variably. ARID2, previously described, is one of the less frequently observed gene changes in CSS. Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. We report here a cohort of 17 individuals with ARID2 variants from the Coffin-Siris/BAF clinical registry and detail their medical challenges as well as developmental progress. Feeding difficulties, hypotonia, and short stature occur often, and hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer. Individuals appear to have mild to moderate intellectual impairment and may carry additional diagnoses such as ADHD. Further phenotypic description of this gene will aid clinicians caring for individuals with this rarer form of CSS.

[Genetic analysis of two children with Coffin-Siris syndrome due to variants of ARID1B gene].

OBJECTIVE: To explore the genetic basis of two children with unexplained psychomotor developmental delay and facial dysmorphisms suggestive of Coffin-Siris syndrome (CSS). METHODS: A boy and a girl suspected for CSS at the 980th Hospital of the People's Liberation Army Joint Service Support Force respectively in July 2019 and January 2021, and seven members from their families, were selected as the study subjects. Clinical data and family history of the children were collected, and detailed physical examination was carried out, in addition with laboratory and related auxiliary examinations. Potential variants and copy number variations (CNVs) were detected by whole exome sequencing (WES) and copy number variation sequencing (CNV-seq). RESULTS: Child 1, an 8-month-old female, had featured microcephaly, atrial septal defect, curving of fifth finger/toe, and low limb muscle tone. Child 2 was a 2.5-year-old male with language delay, social impairment, dense hair but no curving of the fifth fingers. Genetic testing revealed that child 1 had loss of heterozygosity for exons 8 to 21 of the ARID1B gene, which was unreported previously. Family verification showed that both of her parents were of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and American Society of Molecular Pathology (AMP), the variant was rated as pathogenic (PVS1+PS2+PM2-supporting). Child 2 was found to harbor a heterozygous c.4263-6 (IVS17) T>G variant of the ARID1B gene. Transcriptome sequencing confirmed that the variant can affect the normal splicing, resulting in retention of a 5 bp sequence in intron 17. Family verification showed that both of his parents were of the wild type. Based on the guidelines from the ACMG, the variant was rated as pathogenic (PS2+PM2-supporting+PP3+PS3). CONCLUSION: WES and RNA-seq have confirmed the diagnosis of CSS in both children. Discovery of the novel variants has expanded the spectrum of pathogenic mutations underlying CSS, and provided a basis for the genetic counseling.

Ocular manifestations in a cohort of 43 patients with KBG syndrome.

Ophthalmological conditions are underreported in patients with KBG syndrome, which is classically described as presenting with dental, developmental, intellectual, skeletal, and craniofacial abnormalities. This study analyzed the prevalence of four ophthalmological conditions (strabismus, astigmatism, myopia, hyperopia) in 43 patients with KBG syndrome carrying variants in ANKRD11 or deletions in 16q24.3 and compared it to the literature. Forty-three patients were recruited via self-referral or a private Facebook group hosted by the KBG Foundation, with 40 of them having pathogenic or likely pathogenic variants. Virtual interviews were conducted to collect a comprehensive medical history verified by medical records. From these records, data analysis was performed to calculate the prevalence of ophthalmological conditions. Out of the 40 participants with pathogenic or likely pathogenic variants, strabismus was reported in 9 (22.5%) participants, while astigmatism, myopia, and hyperopia were reported in 11 (27.5%), 6 (15.0%), and 8 (20.0%) participants, respectively. Other reported conditions include anisometropia, amblyopia, and nystagmus. When compared to the literature, the prevalence of strabismus and refractive errors is higher than other studies. However, more research is needed to determine if variants in ANKRD11 play a role in abnormal development of the visual system. In patients with established KBG syndrome, screening for misalignment or refractive errors should be done, as interventions in patients with these conditions can improve functioning and quality of life.