Journal of pediatric genetics最新文献

The dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the DNAH5 locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis. Genetic testing indicated that the patient is a compound heterozygote with a pathogenic c.8498G > A (known as pathogenic) on the maternally derived allele and two variants of uncertain significance, c.1206T > A and c.7800T > G, on the paternally derived allele. As PCD is autosomal recessive, we conclude that one, or both, of these paternally derived variants are pathogenic. To our knowledge, this is the first time that the clinical implications of c.1206T > A (p.Asn402Lys) and c.7800T > G (p.Ile2600Met) are documented. Furthermore, we use this case as an example to recommend clinicians to assess for PCD and laterality defects when presented with severe infantile cholestasis. While the association of cholestasis with PCD is relatively uncommon, PCD is a risk factor for increased prevalence of biliary atresia and infections, both of which are known causes of cholestasis in early infancy.

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes, usually occurring in the first 6 months of life. Here, we present a newborn, which was admitted with epileptic seizure on the postnatal second day of life. Sepsis and meningitis were ruled out. Cranial imaging and electroencephalography revealed normal. She developed transient NDM on the follow-up and was diagnosed to carry an ABCC8 mutation. Although the neurological features are more common in patients with KCJN11 mutations, patients with ABCC8 mutations could also represent with subtle neurodevelopmental changes or even with epileptic seizures. The genetic testing and appropriate therapy is important in this patient group for predicting clinical course and possible additional features.

Infantile systemic hyalinosis is a very rare fatal autosomal recessive genetic disorder with a mutation in capillary morphogenesis gene-2- CMG2 /Human anthrax toxin-2 ANTXR2 resulting in spindle cell proliferation, altered collagen metabolism along with extensive deposition of hyaline material in the skin and several tissues. To date only a few cases have been reported in the literature, hence we reported this series. This study is a retrospective chart review of infants diagnosed with infantile systemic hyalinosis from January 2015 through December 2020 at a tertiary care children's hospital in South India. The mean age of presentation was 9.4 months, with a male to female ratio of 1:5. All children were born of consanguineous marriage except one child. All children had symptoms at birth, painful limb movements, multiple joint stiffness, gingival thickening, skin lesions around perianal, perioral areas, and frog-like position. Three (50%) children had stiff skin. Routine tests including complete blood count, liver function test, renal function test, creatine phosphokinase, nerve conduction studies, and metabolic tests were normal in all children. Skin biopsy showed hyalinized collagenous tissue in the dermis. Genetic study results of two cases revealed pathogenic variants in ANTXR2 gene. Infantile systemic hyalinosis should be considered in infants presenting with painful limb movements. The diagnosis helped in avoiding unnecessary investigations and prognostications. The genetic information from proband mutation helped in prenatal diagnosis in two families.

X-linked myotubular myopathy (XLMTM), a centronuclear congenital myopathy secondary to pathogenic variants in the MTM1 gene encoding myotubularin, is typically recognized for its classic and severe phenotype which includes neonatal hypotonia, severe muscle weakness, long-term ventilator dependence, markedly delayed gross motor milestones with inability to independently ambulate, and a high neonatal and childhood mortality. However, milder congenital forms of the condition and other phenotypes are recognized. We describe a 6-year-old boy with a mild XLMTM phenotype with independent gait and no respiratory insufficiency even in the neonatal period. The child has a hemizygous novel splice site variant in the MTM1 gene (c.232-25A > T) whose pathogenicity was confirmed by cDNA studies (exon 5 skipping) and muscle biopsy findings. We also compared the phenotype of our patient with the few reported cases that presented a mild XLMTM phenotype and no respiratory distress at birth, and discussed the potential mechanisms underlying this phenotype such as the presence of residual expression of the normal myotubularin transcript.

Whole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease by sequencing both the exome and the remaining 98 to 99% of the genetic code. In addition to more complete coverage, WGS can detect structural variants (SVs) and intronic variants (SNVs) that cannot be identified by whole exome sequencing (WES) or chromosome microarray (CMA). Other multi-omics tools, such as RNA sequencing (RNA-Seq), can be used in conjunction with WGS to functionally validate certain variants by detecting changes in gene expression and splicing. The objective of this retrospective study was to measure the diagnostic yield of duo/trio-based WGS and RNA-Seq in a cohort of 22 patients (20 families) with pediatric onset neurological phenotypes and negative or inconclusive WES results in lieu of reanalysis. WGS with RNA-Seq resulted in a definite diagnosis of an additional 25% of cases. Sixty percent of these solved cases arose from the identification of variants that were missed by WES. Variants that could not be unequivocally proven to be causative of the patients' condition were identified in an additional 5% of cases.

Ethylmalonic encephalopathy is a rare neurometabolic disorder with central nervous system involvement and vasculopathy. It is presented in infancy with developmental delay, acrocyanosis, petechiae, chronic diarrhea, and early death. This was a retrospective study of confirmed cases of ethylmalonic aciduria from a tertiary care hospital over a period of 5 years from January 2015 to December 2020. Case details including analysis of clinical history, investigations, and outcomes are presented. Of six cases, male-to-female ratio was 4:2. Mean age of presentation was 35.5 months (range: 14-83 months). Consanguinity, global developmental delay, failure to thrive, skin rashes, microcephaly, hypotonia, and exaggerated deep tendon reflexes were observed in all cases. Chronic diarrhea was presented in five cases. The serum levels of C4 carnitine and urinary levels of ethylmalonic acid were increased in all cases. Magnetic resonance imaging (MRI) of the brain showed heterogenous bilateral symmetrical changes in the basal ganglia in five cases, and in one case, MRI could not be done. Genetic testing in two cases showed a homozygous variant in ETHE1 gene. Four children died, while the other two cases showed a decreased in recurrent encephalopathies and diarrhea after starting metronidazole. All children had global developmental delay, failure to thrive, skin rashes, central hypotonia, increased C4 carnitine levels in the serum, and increased ethylmalonic acid in the urine. Chronic diarrhea, acrocyanosis, and basal ganglia change in the MRI of the brain also give important clues for diagnosis. Metronidazole is useful in preventing recurrent episodes of encephalopathy.

Ring chromosome 20 or r(20) syndrome is a rare chromosomal disorder, mainly characterized by childhood-onset drug-resistant epilepsy with typical electroencephalographic findings, followed by mild to severe cognitive-behavioral decline. Recent studies support a possible role of the dopaminergic system in the epileptogenesis of this syndrome. We report the case of a 13-year-old female with mosaic r(20) who showed typical disease onset and evolution and a remarkable electroclinical improvement with zonisamide. Epilepsy related to r(20) is often medically intractable. When valproate and lamotrigine are not effective, zonisamide could be further investigated as a therapeutic option, since it acts as antifocal and it has a potential role in the prevention of dopamine depletion.

Mutations in the FKRP gene result in phenotypes with severe forms of congenital muscular dystrophies (CMD) and limb-girdle muscular dystrophies. We present a Mexican patient with a pathogenic homozygous mutation in the FKRP gene (c.1387A > G, p.Asn463Asp) and CMD with radiological brain anomalies as disseminated hyperintensity lesions and discrete generalized cortical atrophy. These findings have not been reported to the best of our knowledge in other patients with the same mutation. The mutation c.1387A > G, p.Asn463Asp in the FKRP gene has been described to have a founder effect in central Mexico, since all the patients described to date are of Hispanic origin. Therefore, we emphasize studying mutations in the FKRP gene in Hispanic pediatric patients with clinical suspicion of CMD. Clinical and molecular diagnosis of specific CMD subtypes is needed to help clarify the prognosis, management, and genetic counseling to the patient and families.

Meningioma-1 is a transcription activator that regulates mammalian palate development and is required for appropriate osteoblast proliferation, motility, differentiation, and function. Microdeletions involving the MN1 gene have been linked to syndromes including craniofacial anomalies, such as Toriello-Carey syndrome. Recently, truncating variants in the C-terminal portion of the MN1 transcriptional factor have been linked to a characteristic and distinct phenotype presenting with craniofacial anomalies and partial rhombencephalosynapsis, a rare brain malformation characterized by midline fusion of the cerebellar hemispheres with partial or complete loss of the cerebellar vermis. It has been called MN1 C-terminal truncation (MCTT) syndrome or CEBALID (Craniofacial defects, dysmorphic Ears, Brain Abnormalities, Language delay, and Intellectual Disability) and suggested to be caused by dominantly acting truncated protein MN1 instead of haploinsufficiency. As a proto-oncogene, MN1 is also involved in familial meningioma. In this study, we present a novel case of MCTT syndrome in a female patient presenting with craniofacial anomalies and rhombencephalosynapsis, harboring a de novo pathogenic variant in the MN1 gene: c.3686_3698del, p.(Met1229Argfs*87).

Deficiency of interleukin-1 receptor antagonist is a rare autoinflammatory disease that affects infants early in life. It often presents with systemic inflammation, skin and bone involvement. We present a 5-month-old boy who was hospitalized due to generalized erythematous pustular eruption with secondary impetigo, cellulitis, bronchiolitis, and elevated inflammatory markers. The patient was unresponsive to multiple courses of intravenous antibiotics, systemic, and topical steroid medications. The patient was evaluated by dermatology and rheumatology services among other subspecialities. Skin biopsy showed changes consistent with psoriasiform dermatitis, while bone scans showed multifocal osteomyelitis. The patient was started empirically on anakinra with improvement at 72 hours upon administration. This is one of the youngest reported case in the literature to be started on anakinra empirically prior to genetic confirmation of the mutation. A comprehensive literature review revealed that approximately 20 genetically confirmed patients, including our patient, have been reported with this genetic disease. It is imperative to recognize this disease early to achieve adequate response and remission. Therefore, clinical symptoms and the associated differential diagnosis for this disease should be constantly reassessed and reviewed by pediatricians and subspecialists to detect the disease as early as possible and reduce the high morbidity and mortality associated with delayed diagnosis and treatment.