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.

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.

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.

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.

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.

[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.

Anesthetic considerations in the perioperative management of the patient with Jarcho-Levin Syndrome.

Jarcho-Levin syndrome is an eponym used to describe a spectrum of small thoracic skeletal dysplasias with variable involvement of vertebrae and ribs. Initially considered lethal, it is currently compatible with life in its mildest forms. Bone alterations that lead to a restrictive respiratory pattern, recurrent respiratory infections and particular phenotype, can make perioperative anesthetic management difficult. The proper assessment of the airway is of special interest because it presents predictors of a difficult airway, as well as the prevention, early diagnosis and adequate treatment of respiratory failure. We present the case of a patient with Jarcho-Levin Syndrome who underwent vertebral distraction surgery, with its most notable implications in anesthetic management.

A Japanese patient with Teebi hypertelorism syndrome and a novel CDH11 EC1 domain variant.

The gene CDH11 encodes cadherin-11, a Type II cadherin superfamily member that contains five extracellular cadherin (EC) domains. Cadherin-11 undergoes trans-dimerization via the EC1 domain to generate cadherin complexes. Compound heterozygous and homozygous loss-of-function CDH11 variants are observed in Elsahy-Waters syndrome (EWS), which shows characteristic craniofacial features, vertebral abnormalities, cutaneous syndactyly in 2-3 digits, genitourinary anomalies, and intellectual disability. Heterozygous CDH11 variants can cause Teebi hypertelorism syndrome (THS), which features widely spaced eyes and hypospadias. We report a THS patient with a novel CDH11 variant involving the EC1 domain. The patient was a 10-month-old male with normal developmental milestones, but had widely spaced eyes, strabismus, hypospadias, shawl scrotum, broad thumbs (right bifid thumb in x-ray), polysyndactyly of the left fourth finger, and cutaneous syndactyly of left third/fourth fingers. Exome sequencing identified a de novo heterozygous CDH11 variant (NM_001797.4:c.229C > T [p.Leu77Phe] NC_000016.9:g.64998856G > A). Clinical features were consistent with previously reported THS patients, but polysyndactyly, broad thumb, and cutaneous syndactyly overlapped phenotypic features of EWS. THS and EWS may represent a spectrum of CDH11-related disorders. Residue Leu77 in this novel CDH11 variant lines a large hydrophobic pocket where side chains of the partner cadherin-11 insert to trans-dimerize, suggesting that the cadherin-11 structure might be altered in this variant.

Urorectal Septum Malformation Sequence With Retroperitoneal Neuroblastoma: A Case Report of an Unusual Association.

Urorectal septum malformation sequence (URSMS) is an uncommon disease characterized by a failure of the anorectal septum to divide the cloaca and fuse with the cloacal membrane. Complete URSMS is usually lethal in newborn due to severe renal dysfunction and pulmonary hypoplasia. Partial URSMS is compatible with life with a single perineal opening draining a common cloaca with an imperforate anus which amenable to surgical management. Antenatal diagnosis of URSMS is challenging because of multisystem, complex abnormalities involving gastrointestinal, urogenital tract, cardiovascular, and musculoskeletal systems. In this case report, we describe a 15-week male fetus with partial URSMS having a spectrum of multisystem structural anomalies associated with fetal neuroblastoma in retroperitoneal location and adrenal neuroblastoma in situ.

Echidna Splenule: A Case Study of Continuous Splenogonadal Fusion.

Splenogonadal fusion (SGF) is a rare congenital anomaly of an aberrant accessory spleen-gonad connection. We present a rare case of continuous splenogonadal fusion in a full-term male with a left undescended testis, multiple congenital limb anomalies, and syndromic facies. Diagnostic laparoscopy revealed the "Echidna Splenule," a snake-like intraperitoneal splenule coursing from the spleen along the left paracolic region and engulfing an atrophic intra-abdominal testis preventing spontaneous descent and distally herniating into the left open internal inguinal ring. The atrophic testis and Echidna Splenule were resected. Splenogonadal fusion should be considered in children with left undescended testis and concomitant limb and facial anomalies.

Craniosynostosis in molecularly diagnosed Kabuki syndrome: Prevalence and clinical implications.

Kabuki syndrome (KS) is characterized by growth impairment, psychomotor delay, congenital heart disease, and distinctive facial features. KMT2D and KDM6A have been identified as the causative genes of KS. Craniosynostosis (CS) has been reported in individuals with KS; however, its prevalence and clinical implications remain unclear. In this retrospective study, we investigated the occurrence of CS in individuals with genetically diagnosed KS and examined its clinical significance. Among 42 individuals with genetically diagnosed KS, 21 (50%) exhibited CS, with 10 individuals requiring cranioplasty. No significant differences were observed based on sex, causative gene, and molecular consequence among individuals with KS who exhibited CS. Both individuals who underwent evaluation with three-dimensional computed tomography (3DCT) and those who required surgery tended to exhibit cranial dysmorphology. Notably, in several individuals, CS was diagnosed before KS, suggesting that CS could be one of the clinical features by which clinicians can diagnose KS. This study highlights that CS is one of the noteworthy complications in KS, emphasizing the importance of monitoring cranial deformities in the health management of individuals with KS. The findings suggest that in individuals where CS is a concern, conducting 3DCT evaluations for CS and digital impressions are crucial.

Congenital laryngo-tracheo-esophageal clefts: updates from a quaternary care pediatric airway unit.

PURPOSE: To review the operative techniques, outcomes, and complications following surgery in pediatric patients with laryngo-tracheo-esophageal clefts (LTEC). We describe a new combined approach to treat long LTECs. METHODS: Twenty-five patients underwent surgical repair for LTEC from March 2012 to July 2022 at our hospital. Every patient underwent a diagnostic endoscopy under general anesthesia and spontaneous ventilation to assess the LTEC and synchronous aero-digestive comorbidities/malformations. All patients underwent at least one surveillance endoscopy after the repair at our institution. RESULTS: The patients had multiple other malformations, specifically gastro-intestinal, synchronous airway, and cardiac. The cleft distribution according to the modified Benjamin and Inglis classification was type I (n = 5, 20%), type II (n = 6, 24%), type IIIa (n = 8, 32%), type IIIb (n = 4, 16%), and type IVa (n = 2, 8%). The median follow-up was 44.6 months. Five patients (20%) had undergone previous cleft corrective surgery(s). Seven patients (28%) had partial to complete breakdown of the repair, needing additional intervention(s), and two required a combined-open plus endoscopic repair. Preoperatively, most patients (n = 18, 72%) needed a feeding assistance. At latest follow-up, feeding assistance was weaned off in 13 out of 18 patients, which was a 72% improvement. Ten patients (40%) needed ventilation assistance before the surgery. Post-operatively, ventilatory assistance was weaned off in 6 patients, meaning a 60% improvement. CONCLUSION: LTEC are rare malformations, and their management needs precise diagnosis, appropriate surgical planning, and execution, and dedicated post-operative care. Primary and revision repair of long clefts with tracheal extension may require a combined approach.

Delineation of the adult phenotype of Coffin-Siris syndrome in 35 individuals.

Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.

Epilepsy in KBG Syndrome: Report of Additional Cases.

BACKGROUND: KBG syndrome is a genetic disorder characterized by short stature, dysmorphic features, macrodontia, cognitive impairment, and limb anomalies. Epilepsy is an important comorbidity associated with KBG syndrome, although the entire phenotypic spectrum may not be fully appreciated. METHODS: We identified five new patients with KBG syndrome-related epilepsy and compared their phenotype to previously reported cases in the literature. RESULTS: Five patients with KBG syndrome-related epilepsy were identified. Three patients (60%) were male. Median age of seizure onset was 18 months (interquartile range 5, 32). The epilepsy type was generalized in three patients (60%); in two, the epilepsy type was combined (40%), with focal and generalized seizures. In one patient (20%), the epilepsy syndrome was classifiable and the child was diagnosed with myoclonic-atonic epilepsy. All five patients had pathogenic variants in the ANKRD11 gene. Epilepsy was refractory in two patients (40%). No specific antiseizure medication (ASM) was found to be superior. Literature review yielded 134 cases, median age of seizure onset was 4 years, and seizures were generalized (n = 60, 44%), focal (n = 26, 19%), or combined (n = 13, 10%). An epilepsy syndrome was diagnosed in 12 patients (8.8%). In those with documented response to ASM (n = 49), 22.4% were refractory (n = 11). CONCLUSIONS: Our study confirms that few patients with epilepsy and KBG syndrome have an identifiable epilepsy syndrome and generalized seizures are most common. We highlight that epilepsy associated with KBG syndrome may occur before age one year and should be an important diagnostic consideration in this age group.

A Rare Case of Lung Hypoplasia, Cardiac Anomalies and Ovarian Tumour in a Patient with Mayer-Rokitansky-Küster-Hauser Syndrome.

Hypoplasia of the lung is an uncommon congenital abnormality of the respiratory system in contrast to pulmonary agenesis. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is the congenital absence of the upper two-thirds of the vagina and uterus with normal secondary sexual characteristics, ovary and normal karyotype. We report a 31-year-old female patient who presented in 2022 with cough with expectoration, left-side chest pain and breathlessness for 4 years to tertiary hospital, Puducherry, India. She was evaluated for amenorrhoea and diagnosed as MRKH syndrome and the patient underwent right-side oophorectomy for right ovarian torsion with a tumour. Computed tomography pulmonary angiogram and fiberoptic endoscopy were suggestive of left lung hypoplasia and the patient was advised symptomatic treatment for lung hypoplasia and planned for vaginoplasty for which she refused.