Prenatal Diagnosis of c.437-1G>A Mutation in the MAN2B1 Gene in a Family With Alpha-Mannosidosis: Unraveling Clinical Presentation and Treatment Outcomes in a Novel Prenatal Case.

Alpha-mannosidosis is a rare lysosomal storage disorder with progressive impairments in motor functions, skeletal deformities, and immunodeficiency. Enzyme replacement therapy (ERT) should be initiated early to achieve optimal outcomes. This report describes how alpha-mannosidosis diagnosis in a seven-year-old girl led to a successful prenatal diagnosis in the subsequent pregnancy and pre-symptomatic treatment at the early disease stage. The index patient was a seven-year-old girl who was referred with a confirmed diagnosis of alpha-mannosidosis based on the presence of homozygous c.437-1G>A mutation in the MAN2B1 gene. A prenatal diagnosis was made in the subsequent pregnancy through molecular analysis, which revealed the same homozygous variant. The patient was treated at the fifth week of age and showed mild skeletal involvement and normal development at ERT initiation. At 11 months of age, the ERT level increased to 15.8 µmol/l/h. The motor assessment showed that the patient was developmentally normal and was able to maintain her sitting and walking for a few steps only. Prenatal molecular screening in affected families can allow for the early identification and implementation of appropriate management strategies for alpha-mannosidosis.

Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis.

BACKGROUND: Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. METHODS: We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. RESULTS: We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. CONCLUSION: Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

Genotype and Phenotype of Adenosine Deaminase 2 Deficiency: a Report from Saudi Arabia.

Adenosine deaminase 2 deficiency (DADA2), a rare and potentially fatal systemic autoinflammatory disease, is characterized by low or lack of ADA2 activity due to ADA2 mutations. DADA2 symptoms are variable and include vasculitis, immunodeficiency, and cytopenia. Minimal data are available from Saudi Arabia. This retrospective study conducted at seven major tertiary medical centers examined the phenotypic and genotypic variabilities, clinical and diagnostic findings, and treatment outcomes among 20 Saudi patients with DADA2 from 14 families. The median age of the study cohort was 9.5 years (4-26 years). The clinical presentation was before the age of 5 months in 25% of patients. Homozygous c.1447-1451del mutation was the most frequent ADA2 alteration (40%), followed by c.882-2A:G (30%). All tested patients exhibited absent or near-absent ADA2 activity. Phenotypic manifestations included stroke (40%), hematological abnormalities (95%), lymphoproliferation (65%), and recurrent infection (45%). Five and three patients had extracranial vasculitis features and Hodgkin lymphoma, respectively. Atypical manifestations included growth retardation (30%) and transverse myelitis. Anti-tumor necrosis factor (anti-TNF) therapy was the main treatment. Some patients underwent blood transfusion, splenectomy, cyclosporine and colony-stimulating factor therapies, and hematopoietic stem cell transplantation due to anti-TNF therapy failure. Fulminant hepatitis and septic multiorgan failure caused mortality in three patients. Thus, this study revealed the variability in the molecular and clinical characteristics of DADA2 in the study cohort with predominant aberrant hematological and immunological characteristics. Consensus diagnostic criteria will facilitate early diagnosis and treatment. Additionally, disease registries or large prospective studies are needed for evaluating rare disease complications, such as cancer.

A novel variant of RBCK1 gene causes mild polyglucosan myopathy.

Homozygous or compound heterozygous pathogenic variants of the RBCK1 gene can result in a systemic disorder characterized by the accumulation of complex carbohydrate molecules, namely polyglucosan bodies in the muscular tissues. The role of this gene in the pathophysiology of the disorder at the molecular level remains unclear. Being a very rare disorder, the medical knowledge is based on just a few reported cases. Here we report a 7-year-old girl who presented with exercise intolerance and hepatosplenomegaly. Her liver profile was constantly raised. The genetic investigation has revealed a variant of the RBCK1 gene of unknown significance, which has later been confirmed as pathogenic via a variety of clinical, genetic, and histopathological approaches. More importantly, it is evident that the availability of sophisticated genetic testing, such as whole-exome sequencing, has significantly improved the knowledge of and diagnosis of many rare metabolic disorders.

The first Saudi baby with classic homocystinuria diagnosed by universal newborn screening.

Classic homocystinuria (CH) is an inborn error of metabolism caused by cystathionine beta-synthase enzyme deficiency. Affected patients present with intellectual disability and other comorbidities. If diagnosed early in infancy and started treatment, inevitable complications can be prevented. Newborn screening (NBS) uses tandem mass-spectroscopy (MSMS) to measure the amino acid levels. In CH, the first-tier screening test is the measurement of methionine by MSMS. If methionine remained elevated in the recall sample, plasma level for homocysteine is performed. A newborn infant underwent routine NBS in our institute that showed elevated methionine in the first and the recall sample. Thereafter, total serum homocysteine was found to be elevated, consistent with the diagnosis of CH. An early medical and dietary management was commenced for this first Saudi baby diagnosed with homocystinuria by universal NBS. This report demonstrates that NBS for CH is feasible and effective in preventing the disease burden.

Wolman's disease presenting with secondary hemophagocytic lymphohistiocytosis: a case report from Saudi Arabia and literature review.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome that is characterized by strong activation of the immune system from hyperinflammatory cytokines. Symptoms of HLH patients include fever, hepatosplenomegaly, cytopenia, and hyperferritinemia. Inherited HLH is classified as primary, whereas secondary HLH (sHLH) occurs when acquired from non-inherited reasons that include severe infection, immune deficiency syndrome, autoimmune disorder, neoplasm, and metabolic disorder. Wolman's disease (WD) is a rare and fatal infantile metabolic disorder caused by lysosomal acid lipase deficiency, that exhibits similar clinical signs and symptoms as HLH. This paper reports the case of an infant diagnosed with WD and who presented with sHLH. CASE PRESENTATION: A 4-month-old infant presenting with hepatosplenomegaly, failure to thrive, and other abnormalities. WD diagnosis was confirmed by the presence of the LIPA gene homozygous deletion c.(428 + 1_967-1)_(*1_?)del. The infant also met the HLH-2004 diagnostic criteria. CONCLUSIONS: Metabolic disorder such as WD should be investigated in infants fulfilling the HLH criteria to diagnose the underlying condition. More studies are needed to understand the link between WD and sHLH and to identify appropriate therapies.

Inferior alveolar nerve damage secondary to orthodontic treatment: A systematic scoping review.

BACKGROUND: Neurosensory impairment is a common complication following inferior alveolar nerve (IAN) damage. OBJECTIVE: To document and report the various causes, diagnosis, and management of IAN damage secondary to orthodontic treatment. METHODS: An electronic search for studies that reported IAN damage in patients undergoing orthodontic treatment was performed up to July 15, 2020 using MEDLINE, Embase, and PubMed databases. Descriptive analyses and linear regression model were performed. RESULTS: A total of 15 case reports were identified including 16 patients with an overall mean age of 23.3. All the included studies reported temporary sensory alterations which manifested as anesthesia (19%, n = 3), paresthesia (75%, n = 12), or combined (6%, n = 1). The majority of cases managed by stopping the orthodontic force (75%, n = 12), followed by appliance adjustments (19%, n = 3), providing a bite plate (13%, n = 2), and/or providing pharmacological management (38%, n = 6). Full recovery median duration reported in all cases following the aforementioned managements was 17.5 days. CONCLUSIONS: IAN damage secondary to orthodontic treatment is emerging in the literature in recent years. Identifying high risk patients with close proximity to the IAN canal is a must to formulate a proper treatment plan to avoid such complications.

Proteus syndrome caused by novel somatic AKT1 duplication.

Proteus syndrome (PS) is a rare overgrowth disorder that presents with asymmetrical growth of the bone and fat tissues following a mosaic pattern mutation. The estimated worldwide incidence is approximately one in one million live births. Proteus syndrome causes disfigurement and psychological impact through its effects on somatic tissue. Due to its rarity and diversity of tissues involved, it represents a significant challenge to caregivers and multidisciplinary medical teams. Here, we report a Saudi girl, with a large left cervical mass discovered antenatally. This mass was identified as a growing cystic hygroma, and she had features of overgrowth and hemangiomas. Whole exome sequencing was negative from the blood lymphocytes and affected tissue sample.  However, deletion duplication analysis from tissue shows a novel mosaic somatic mutation of the AKT1 gene. Somatic mutation remains an obstacle, and the geneticist has an essential role in its management, providing an established genetic diagnosis, prognosis, and family counselling.

Development and validation of a score for emergency intervention in patients with acute renal colic secondary to ureteric stones.

Objectives: To develop and validate a scoring system to assess the need for emergency intervention (EI) in patients with uncomplicated acute renal colic (ARC) due to ureteric stones. Patients and methods: From May 2017 to April 2019, 382 adult patients presented to emergency department with ARC due to ureteral stones diagnosed by non-contrast computed tomography. Patients with solitary kidney, complications secondary to obstruction (intractable vomiting, fever or sepsis), bilateral ureteric stones, Stage ≥3 chronic kidney disease or those who underwent treatment of urolithiasis within the past 6 months were excluded. EI was performed in cases with persistent or recurrent pain despite analgesics. Multivariate analysis was performed for the first 200 patients to detect risk factors for EI. The score was developed from significant factors. Sensitivity and specificity of the ARC score were calculated using receiver operator characteristic (ROC) curve analysis. The data of last 182 patients were used for validation of the score. Results: In the first 200 patients, EI was needed in 119 patients (59.5%) and included ureteric stents in 92, ureteroscopy in 25 and percutaneous nephrostomy in two. Significant factors for EI were stone location (relative risk [RR] 3.34, P = 0.026), creatinine level (RR 1.04, P < 0.001), leucocyte count (RR 1.69, P < 0.001), and stone length (RR 1.85, P < 0.001). A score using these four variables was developed. The ARC score sensitivity was 86%, specificity was 80% and the area under the ROC curve was 0.902. Validation of the score showed strong correlation between ARC score and need for EI (r = 0.788, P < 0.001). Conclusions: The ARC score is a validated, highly sensitive and specific novel score to determine the need for EI in patients with uncomplicated ARC secondary to ureteric stones. Abbreviations: ARC: acute renal colic; AUC: area under the ROC curve; CDR: clinical decision rules; CKD: chronic kidney disease; ED: emergency department; EI: emergency intervention; MET: medical expulsive therapy; NCCT: non-contrast CT; PCNL, percutaneous nephrolithotomy; ROC: receiver operator characteristic; S.T.O.N.E.: stone size (S), tract length (T), obstruction (O), number of involved calyces (N), and essence or stone density (E); SWL: extracorporeal shockwave lithotripsy; URS: ureteroscopy; WBC: white blood cell.

An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia.

Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (n = 58), neonatal respiratory distress (NRD) (n = 2), laterality defect (LD) (n = 6), and combined LD/SPI (n = 15). Biallelic likely deleterious variants were also encountered in AKNA and GOLGA3, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in ITCH, and a pathogenic variant in CEP164 causing Bardet-Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help "democratize" the diagnosis of PCD, which is currently limited to highly specialized centers.

A de novo splicing variant supports the candidacy of TLL1 in ASD pathogenesis.

Congenital heart disease (CHD) is the most common type of birth defects with family- and population-based studies supporting a strong hereditary component. Multifactorial inheritance is the rule although a growing number of Mendelian forms have been described including candidates that have yet to be confirmed independently. TLL1 is one such candidate that was proposed in the etiology of atrial septal defect (ASD). We describe a girl with congenitally corrected transposition of the great arteries (ccTGA) and ASD secundum whose whole-exome sequencing (WES) revealed a de novo splicing (c.1379-2A>G) variant in TLL1 as well as an inherited truncating variant in NODAL. The identification of this dual molecular diagnosis both supports the candidacy of TLL1 in ASD pathogenesis and highlights the power of WES in revealing multilocus cardiac phenotypes.

Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

Grafted tubularised incised-plate urethroplasty: An objective assessment of outcome with lessons learnt from surgical experience with 263 cases.

OBJECTIVE: Snodgrass urethroplasty remains the preferred technique in primary distal hypospadias but development of meatal stenosis often limits distal extension of the midline incision of the urethral plate (MIUP), which remains a limiting factor in reconstructing an apical neomeatus (NM). We here-in assess the cosmetic and functional outcome with distal extension of the MIUP in grafted tubularised incised-plate urethroplasty (G-TIP) repair. PATIENTS AND METHODS: This prospective study included the surgical experience of 263 cases of primary hypospadias operated upon between 2012 and 2015. The G-TIP technique included standard steps of Snodgrass urethroplasty, including degloving and harvesting of glans wings, followed by MIUP that was extended distally beyond the margins of the urethral plate (UP) into the glans. The incised bed was grafted with a free preputial skin graft and fixed to the bed with polydioxanone 7-0 suture. The UP was tubularised and the suture line reinforced with a Dartos flap. The urethral catheter was removed at 7-10 days after the repair and the outcome was assessed at follow-up using the Hypospadias Objective Scoring Evaluation (HOSE) system. RESULTS: An apical NM was achieved in 96% of the patients with a 3.7% incidence of urethrocutaneous fistula. The presence of suture tracks and graft at the margins of the NM were seen in the initial 4% and 5% of cases, respectively. Acceptable cosmetic results, with objective HOSE scores of >14, were achieved in 96% of cases. CONCLUSION: The G-TIP repair is a straightforward and feasible technique facilitating reconstruction of an apical NM, with an optimum outcome based on HOSE scoring. However, multicentre data are needed for undertaking comparative analysis and to assess the universal applicability of this technique in primary hypospadias.