Recurrent Skin Ulcers with Facial Dysmorphism and Sinopulmonary Infections: Thinking Beyond Hyper-IgE Syndrome

Prolidase deficiency (PD) is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. It occurs due to the mutations in the prolidase gene (PEPD) that result in loss of prolidase activity. We reported here a child who had presented with features compatible with hyper-immunoglobulin E syndrome (HIES) like recurrent skin ulcers, recurrent infections, facial dysmorphism, retained primary teeth, and elevated levels of immunoglobulin E levels but with normal flow cytometric assays, which was later diagnosed as PD.

The Utilization of MS-MLPA as the First-Line Test for the Diagnosis of Prader–Willi Syndrome in Thai Patients

Prader–Willi syndrome (PWS) is a genetic disorder caused by the expression disruption of genes on the paternally inherited allele of chromosome 15q11.2-q13. Apart from clinical diagnostic criteria, PWS is confirmed by genetic testing. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is one of the molecular techniques used to analyze this syndrome. This study aimed to evaluate the concordance of the test results of MS-MLPA with conventional techniques in the diagnosis of PWS in Thai patients. Forty leftover specimens from routine genetic testing (MS-PCR and FISH) were tested to obtain MS-MLPA results. By comparison, perfect concordance was shown between the result of MS-MLPA and those of conventional techniques. In conclusion, MS-MLPA is an accurate and cost-effective assay that can be used to confirm PWS diagnosis with explicit deletion of affected genes.

Recurrent Bilateral Lower Motor Neuron Type of Facial Palsy with Hearing Impairment: Hyperphosphatemic Familial Tumoral Calcinosis

Hyperphosphatemic familial tumoral calcinosis (HFTC) presents with varied neurological manifestations that have been reported in the literature like facial palsy, vision and hearing impairment, stroke, and headache. In this article, we reported a 12-year-old girl child patient with recurrent facial weakness with bilateral hearing impairment and multiple ulcerative lesions on lower limbs and elbows. On examination, she had lower motor neuron (LMN) facial palsy with conductive hearing loss. The investigations showed hyperphosphatemia (9.3 mg/dL) with normal serum calcium (10.4 mg/dL), alkaline phosphatase (147.9 U/L), parathyroid hormone (23.12 pg/mL), and renal function tests. Elevated serum calcium and phosphorus product (96.72 mg2/mL2) and elevated renal tubular reabsorption of phosphate (TMPxGFR) value (9.16) were noted. Skeletal survey showed hyperostosis in the long bone diaphysis, vertebrae, ribs, pelvic bone, skull, and facial bones with narrowing of cranial ostium, characteristically without any peri-articular soft tissue calcifications. An angiogram showed multiple intravascular calcifications. She was managed with a low-phosphate diet, sevelamer, niacinamide, acetazolamide, sucroferric oxyhydroxide to lower serum phosphate level, and topical sodium thiosulfate ectopic cutaneous calcification. Exome sequencing showed novel homozygous inframe deletion of ACG in FGF23 gene exon 3 at c.374_376 delins position (p. Asp125del) in the proband and a mutation in the heterozygous state in the mother and elder sibling, thus confirming a molecular diagnosis of HFTC. Our case had a unique neurological presentation of recurrent bilateral lower motor nerve facial palsy, hearing loss, multiple ectopic cutaneous calcifications without peri-articular deposits, multiple intravascular, intracranial, and vertebral endplate calcification, which has not been reported earlier. The proband showed a novel pathogenic variant suggesting an expanding phenotype of HFTC.

SWI/SNF-Related SMARCA2 Gene Mutation Associated with Nicolaides–Baraitser's Syndrome: Follow-up Study

Nicolaides–Baraitser's syndrome is a rare, dominantly inherited well-delineated syndrome caused by mutations in the SMARCA2 gene which is located on the small arm of chromosome 9. In this study, a de novo missense variant, which was identified in a 3-year-old boy by whole exome sequencing is reported. The de novo heterozygous V1198M missense variant in SMARCA2 gene in exon 25 is novel. Identifying the condition is crucial for the long-term management and family counseling. Follow-up over 4 years revealed improvements in overall performance.

Compressive Myelopathy Secondary to TRPV4 Skeletal Dysplasia: Spondylometaphyseal Dysplasia, Kozlowski Type

Transient receptor potential vanilloid 4 channel (TRPV4) gene mutations have been described in skeletal system and peripheral nervous system pathology. The case described here is a 9-year-old male child patient, born to a nonconsanguineous marriage with normal birth history who had difficulty in walking and stiffness of joints for the last 7 years, and progressive weakness of all four limbs and urine incontinence for 1 year following falls. Physical examination showed below-average weight and height and short trunk. Musculoskeletal examination revealed bony prominence bilaterally in the knee joints and contractures in knee and elbow joints with brachydactyly; muscle tone was increased, with brisk deep tendon reflexes. Skeletal survey showed platyspondyly with anterior beaking with metaphyseal dysplasia. Magnetic resonance imaging of the spine revealed atlantoaxial instability with hyperintense signal changes at a cervicomedullary junction and upper cervical cord with thinning and spinal canal stenosis suggestive of compressive myelopathy with platyspondyly and anterior beaking of the spine at cervical, thoracic and lumbar vertebrae. Exome sequencing revealed a heterozygous de novo variant c.2389G > A in exon 15 of TRPV4, which results in the amino acid substitution p.Glu797Lys in the encoded protein. The characteristics observed indicated spondylometaphyseal dysplasia, Kozlowski type (SMD-K). The child underwent surgical intervention for compressive myelopathy by reduction of atlantoaxial dislocation with C1 lateral mass and C2 pars fusion using rib graft and fixation using screws and rods. To conclude, for any child presenting with progressive kyphoscoliosis, short stature, platyspondyly, and metaphyseal changes, a diagnosis of SMD-K should be considered and the patient and family should be advised to avoid spinal injuries.

Frameshift Variant in ARID2 in a Chilean Individual with Coffin–Siris Syndrome Phenotype

Coffin–Siris syndrome (CSS) is one of the several causes of intellectual disability (ID) and, since its first description, has posed diagnostic challenges given its variability and phenotypic overlap with other alterations of chromatin-remodeling-associated syndromes. It is genetically heterogeneous, and causative mutations are detected in less than 70% of cases. The different subtypes of the syndrome described to date are caused by mutations in genes that encode subunits of the SWI/SNF chromatin-remodeling complex, which plays an essential role in the regulation of gene expression during embryogenesis. Whole exome sequencing (WES) has allowed the identification of pathogenic mutations in these genes, including ARID2. ARID2 is one of the primary components of the SWI/SNF complex and has been associated with ID and phenotypes similar to CSS for the first time in 2015. Fifteen published case reports have identified loss-of-function mutations, suggesting that the underlying pathogenic disease mechanism is haploinsufficiency of ARID2.We herein presented the case of an 8-year-old Chilean girl with clinical suspicion of CSS, in whom a novel frameshift variant in ARID2 was identified by WES. She was the first reported case in Latin America to our knowledge and her phenotype displays the main clinical features suggestive of CSS described in other patients with ARID2 variants. However, she did not present behavioral abnormalities, a characteristic frequently reported in the majority of patients with ARID2 variants, and also had some features, such as sparse scalp hair, which is frequently reported as a manifestation of CSS, but is uncommon in this new group of patients.

Genetics Landscape of Nonsyndromic Hearing Loss in Indian Populations

Congenital nonsyndromic hearing loss (NSHL) has been considered as one of the most prevalent chronic disorder in children. It affects the physical and mental conditions of a large children population worldwide. Because of the genetic heterogeneity, the identification of target gene is very challenging. However, gap junction β-2 (GJB2) is taken as the key gene for hearing loss, as its involvement has been reported frequently in NSHL cases. This study aimed to identify the association of GJB2 mutants in different Indian populations based on published studies in Indian population. This will provide clear genetic fundamental of NSHL in Indian biogeography, which would be helpful in the diagnosis process.

Alstrom's Syndrome: An Experience of Tertiary Care Center

Alstrom's syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision, hearing impairment, cardiomyopathy, childhood obesity, diabetes mellitus type 2, dyslipidemia, pulmonary, hepatic, and renal failure besides systemic fibrosis. Biallelic pathogenic variants in ALMS1 gene cause AS. Retrospective study (1990–2017) included 12 Saudi patients with AS based on their phenotype, biochemical markers, and genotype. The study was approved by Fisal Specialist Hospital and Research Centre, Riyadh (RAC number 2131129) on October 2, 2012. This study showed clinical and genetic heterogeneity; six patients showed a founder mutation (IVS18–2A > T in exon 19), whereas six others showed private mutations. AS in Saudi Arabia is underdiagnosed probably because of its variable clinical manifestations. We report 12 Saudi patients with AS to enhance the awareness about this syndrome.

A Novel Mutation Diagnosing in Allan–Herndon–Dudley's Syndrome

Allan–Herndon–Dudley's syndrome (AHDS) is a rare X-linked recessive disease that causes abnormal serum thyroid function tests, severe hypotonia, intellectual disability, and motor deficit due to a mutation in the monocarboxylate transporter 8, which is a thyroid hormone transporter. A 6-month-old male patient presented to our outpatient clinic with a serious hypotonia complaint. With a preliminary diagnosis of AHDS, a molecular genetic examination was performed. The molecular genetic analysis detected a new previously unidentified variant in the SLC16A2 gene. This case has been presented to report the AHDS, which is a rare cause of hypotonia in patients presenting/consulting with severe hypotonia, global developmental delay, and abnormal thyroid function test results. Besides, a novel pathogenic mutation in the SLC16A2 gene has been described in the present article.

A Genotyped Case of Townes–Brocks Syndrome with Absent Pulmonary Valve Syndrome from Turkey

Townes–Brocks syndrome (TBS) is a rare syndrome characterized by triad of anal, ear, and thumb anomalies. Further malformations/anomalies include congenital heart diseases, foot malformations, sensorineural and/or conductive hearing impairment, genitourinary malformations, and anomalies of eye and nervous system. Definitive diagnosis for TBS is confirmed by molecular analysis for mutations in the SALL1 gene. Only one known case of TBS with absent pulmonary valve syndrome (APVS) has been previously described to our knowledge. Here, we report a newborn diagnosed with TBS with APVS and tetralogy of Fallot (TOF) who was found to carry the most common pathogenic SALL1 gene mutation c.826C > T (p.R276X), with its surgical repair and postoperative follow-up. To our knowledge, this is the first genotyped case of TBS from Turkey to date. TBS should be suspected in the presence of ear, anal, and thumb malformations in a neonate. If a patient with TBS and TOF-APVS needs preoperative ventilation within the first months of life, this implies prolonged postoperative intubation and increased risk of mortality.