Background: Trisomy 18 is an aneuploidy that has historically been associated with early mortality However, recently parents of children with complex conditions are more often pursuing life-prolonging medical interventions. The increasing use of neonatal intensive care has led to longer lifespans in infants affected by trisomy 18, allowing for later complications to emerge. While many comorbidities have been reported in the literature, tethered cord has rarely been reported in this population. This study examines the potential relationship between trisomy 18, tethered spinal cord, and related urinary tract complications. Methods: A retrospective chart review of subjects admitted to a single quaternary academic medical center with trisomy 18 receiving resuscitative care from 2014-2024 was performed. Charts were analyzed for spinal, bladder, and renal imaging, and for radiographic concern for tethered cord. Clinical outcomes were reviewed, including urinary tract infections and other findings concerning for neurogenic bladder. Results: Ten live-born subjects with trisomy 18 who received initial intensive care were included. The cohort had a mean lifespan of approximately 151 days. Three subjects (30%) received spinal imaging, and all three had radiographic evidence of spinal cord tethering. Six subjects (60%) were diagnosed with urinary tract infections during their initial hospital stay, substantially higher than reported neonatal intensive care unit prevalence rates. Conclusions: These results indicate a potentially increased risk of urinary tract infections among patients with trisomy 18. When caring for this population, clinicians should be aware of the possible presence of pathophysiologic mechanisms that are not yet well-documented, including neurogenic bladder and a tethered cord.
Background: HPRT1-related disorders are X-linked metabolic disorders of the purine pathway caused due to mutations in the hypoxanthine-guanine phosphoribosyl transferase (HPRT1) gene and present with features of dyskinetic cerebral palsy, self-mutilation/behavioral abnormality, and hyperuricemia in variable severity. Objective: Describe the clinical characteristics and treatment outcome of a series of 6 children with Lesch-Nyhan disease. Methods: Retrospective chart review from September 2022 to July 2024 of six molecularly confirmed cases of Lesch-Nyhan disease from India. Results: A total of 6 boys are described here. The mean age of onset was since birth, the age of diagnosis was 2 years 7 months, and the current age was 4 years 11 months. Features of developmental delay with motor predominance, dystonia, behavioral abnormality, and hyperuricemia (mean level 8.82 mg/dl) were seen in all. Self-mutilation was present in one while abnormal urine colour was noted in two cases. Routine metabolic tests were normal in all children. Seizures were noted in three children, with good response to therapy. The disease-causing mutation was identified in all: three missense variants and three loss of function variants: one each of nonsense, frameshift, and splice site. Treatment with Allopurinol resulted in a reduction of uric acid and only mild improvement in neurological features. Conclusion: The presentation of Lesch-Nyhan's disease usually mimics that of dyskinetic cerebral palsy. Normal imaging and increased uric acid give important clues for the diagnosis. Self-mutilation and abnormal urine color may not be always present. Early diagnosis helps in initiating treatment and preventing recurrence in the family.
Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder caused by biallelic mutations in the SLC2A2 gene, characterized by proximal renal tubular dysfunction, hepatomegaly, and growth failure. We report five patients from three unrelated families in North India, including a sibling trio with significant intrafamilial variability and one of the few documented successful pregnancies in an affected female. Genetic testing identified a recurrent nonsense variant c.1093C>T (p.Arg365Ter) in two families and a missense variant c.1330T>C (p.Trp444Arg) in the third. The phenotypic spectrum ranged from mild growth delay to severe skeletal involvement and poor therapeutic response. Our report underscores the clinical variability of FBS, the importance of molecular diagnosis, and the need for long-term monitoring.
Objective: Many rare diseases are usually misdiagnosed or diagnosed late. Delays in diagnosis have led to delayed treatment, resulting in poor outcomes. This study aims to shed light on the Indian scenario and help formulate schemes for early diagnosis, management of rare diseases and to uncover the unmet needs of the families of children with rare diseases. Methods: The target population were families with a child (17 years or younger) with any rare disease coming to SPINPH, Jaipur. The first author met face-to-face with the parents and they were invited to answer the questionnaire. The questionnaires were checked for completeness and statistical analysis done. Results: In this study, we found that 63% of patients believed the diagnosis was delayed and 47% patients had to see >= 6 doctors to get the correct diagnosis. Overall 67% patients did not get the correct diagnosis for more than 3 months since the onset of symptoms, while 10% patients had to wait more than 1 year. Maximum diagnostic delay was found in children with Inborn Error of Metabolism. Conclusion: As it is difficult to diagnose rare diseases, they are mostly missed at the primary healthcare level due to the non-availability of specialists and hence timely referral to higher center is the key to early diagnosis. As IEMs are usually misdiagnosed, an extensive newborn screening program for some common IEM, can help in solving a part of the problem.
Williams-Beuren syndrome (WBS), commonly abbreviated to Williams syndrome, is well described in the literature regarding its typical clinical presentation, which is the result of a heterozygous deletion within the genetic sequence located on chromosome 7q11.23. The gene for elastin (ELN) is located within this DNA sequence. Patients with WBS exhibit multi-organ involvement including cardiac abnormalities such as supravalvular aortic stenosis and connective tissue disorders due to the disruption of ELN.1 In this case, we present an infant born with extensive infantile hemangiomas, including cutaneous and organ involvement, verified by skin biopsy, and abnormal hepatic vessels. Our patient received an extensive workup and treatment for her skin findings as a newborn but was not diagnosed with WBS until the age of two years old. The diagnosis of WBS was confirmed by chromosomal microarray. Beyond arterial narrowing and associated hypertension, there has been no association between WBS and other vascular anomalies previously noted in the literature.
This cohort study of 48 unrelated probands with rare monogenic childhood hypotonia was designed to assess the clinical presentations, spectrum of disorders, and utility of exome sequencing in selected cases where preliminary genetic tests did not sufficiently explain the etiology. Clinically 56.3% of the cases appeared to be of peripheral hypotonia, 33.3% cases were of central hypotonia, and remaining 10.4% were mixed hypotonia cases. Exome sequencing was able to provide a diagnosis in 52.1% cases in the entire cohort of rare monogenic childhood hypotonia. Majority (41.6%) of the probands had a clinical diagnosis of congenital myopathy/muscular dystrophy in the cohort of which 60% arrived at a molecular diagnosis. LMNA-related and LAMA2-related congenital muscular dystrophies were the most common genes identified in the cohort. We also report 12 novel variants and provide illustrative rare phenotypes for better delineation of specific disorders.
The Gorham-Stout's disease, also known as massive osteolysis or evanescent bone disease; is an extremely rare disease characterized by a proliferation of intraosseous lymphatic channels causing progressive osteolysis. Usually, surgery, sclerotherapy and radiotherapy have been reserved for local and symptomatic control of the disease, while medical treatments have presented variable results that are not entirely satisfactory according to literature. The recent identification of germline-activating somatic mutations in the PIK3CA gene has opened the way to treatment with mTOR inhibitors, being Sirolimus an effective option with a low incidence of serious adverse effects. We present a patient diagnosed with GSD and treated with Sirolimus who showed clinical and radiological improvement at 8 months of follow-up.
Disorders of carbohydrate and lipid metabolism are the leading underlying etiologies of hepatomegaly and hepatic steatosis in young children. With ever increasing access to genetic analysis methods, previously hitherto unknown and under-diagnosed entities like transient infantile hypertriglyceridemia, have been recently added as one of the differential diagnosis for the same. As per the available literature, this entity has been reported to have a benign course, however with increasing number of reported cases, there is yet much more to explore. We hereby present two such pediatric cases presenting with infantile onset hepatomegaly and hepatic steatosis along with a review of literature for this entity.
In view of significant overlapping clinical features in mucopolysaccharidoses (MPS) subtypes, clinicians face difficulty in differential diagnosis, thus requiring the need for a machine learning-based clinical tool for the provisional diagnosis of MPS subtypes. Out of 520 patients with suspicion of MPS, 296 patients were identified with MPS types. To develop the model, we took 53 clinical symptoms of MPS patients (n=255) into account for differential diagnosis. The diagnosis was based on enzyme testing. Among mucopolysaccharidoses, MPS I was the most prevalent. Different machine learning tools were examined, and classification and regression tree (CART) emerged as the most promising. The total prediction accuracy in determining the subtype of MPS was 79.92%, with a precision of 89.31%. Phenotype-based provisional diagnosis of MPS can be emerging as a useful effective tool for clinicians, thus eliminating the need to perform a whole panel of enzymes. Improved therapeutic efficacy can be attained through early diagnosis and specific intervention. Additionally, this study estimated the prevalence of MPS disorders and established the disease-specific cut-offs of that can affected from carriers.
WDFY3 is a critical gene involved in neuronal migration, autophagy, and vesicular transport during brain development. Pathogenic variants in WDFY3 gene are associated with a range of neurodevelopmental disorders, including autism spectrum disorder ASD, epilepsy, and intellectual disability. We present here a case of a female child with a de novo heterozygous WDFY3 variant (c.10189A>T; p.Thr3397Ser), identified through whole exome sequencing. The patient presented with microcephaly, global developmental delay, and epilepsy. Despite the presence of microcephaly, neuroimaging (MRI) revealed no significant abnormalities, a finding consistent with previous reports. Previous studies suggests that WDFY3 haploinsufficiency alters synaptic density and mitochondrial localization, contributing to neurodevelopmental impairments. In the current patient epilepsy was partially controlled with levetiracetam, and developmental therapies were enhanced with cannabidiol, resulting in some progress. This case expands the clinical spectrum of WDFY3-related disorders, emphasizing its key role in neurogenesis and synaptic plasticity. Early genetic diagnosis and personalized therapeutic approaches are crucial in managing such complex neurodevelopmental conditions. Further research is needed to explore the genotype-phenotype correlations and potential interventions for WDFY3-associated disorders.
Biotin-thiamine responsive encephalopathy type 2 (BTBGD) is caused by biallelic pathogenic variants in SLC19A3 (solute carrier family 19). Among three clinical phenotypes of BTBGD (early infantile onset, classical and adult onset) early infantile form of BTBGD is associated with poor prognosis. Here in we report twins with BTBGD early onset infantile Leigh syndrome phenotype unresponsive to thiamine and biotin therapy, progressive neuroimaging changes and early death. Both twins carried biallelic truncating novel c.307dupG / p.Val103fs*121 variant in SLC19A3 gene and we discuss reasons of unresponsiveness.
Brown-Vialetto-Van Laere (BVVL) syndrome is neurodegenerative condition, characterised by ponto-bulbar palsy and sensori-neural hearing loss. Since, this is a rare condition with common sign and symptoms, diagnosis is usually missed or delayed. The above condition is Riboflavin transporter defect which responds to riboflavin therapy. Molecular study confirmed the diagnosis and found recurrent pathogenic variation c.1238 C>A; p Val 413 Asp in exon 5 of SLC52A3 gene in present case. We tabulated all Indian cases of BVVL and highlighted their clinical features and genotype. BVVL type 1 is the most common type, reported from Indian patients.
Background: Kleefstra syndrome (KS) is a rare genetic syndrome that develops due to haploinsufficiency of the euchromatic histone methyltransferase 1 gene and is mostly characterized by hypotonia, developmental delays and intellectual disorders. We aimed to report the potential effectiveness of a 12-week intensive physiotherapy (PT) program provided to a child with KS and to present the twoyear longitudinal follow-up results. Case Presentation: A 1-year-old male child diagnosed with KS was admitted. The age-specific individualized PT program was implemented for 12-week and the child was longitudinally followed-up. The Bayley Scales of Infant and Toddler Development-Third-Edition (Bayley-III), PedsQL (TM) Family Impact Module (FIM), PedsQL (TM)-Parent-Report for Infants (Ages 13-24 months), PedsQL (TM)- Parent-Report for Toddlers (Ages 2-4 years) and Sensory Profile-2 Caregiver Questionnaire were implemented at baseline, 3 months later, at 2 years of age, and at 3 years of age. The child demonstrated significant improvements in gross/fine motor and cognitive development and more moderate improvements in language development after the intensive PT program. However, both after intensive PT and at the follow-up at 2 and 3 years of age, all Bayley-III scores were <70 indicating severe neurodevelopmental delay. The intensive 12-week PT program improved the child's health-related quality of life (HRQoL) and positively influenced the family's emotional well-being, daily activities, and overall quality of life. However, these gains gradually diminished over time, with HRQoL scores stabilizing for the family but largely declining for the child at the two- and threeyear follow-ups. Conclusion: Intensive PT in the early period may promote the earlier acquisition of motor milestones in children with KS.
