Arteriovenous malformations as a presenting sign of PTEN hamartoma tumor syndrome: A case series.

High-flow vascular malformations have been associated with multiple syndromes including capillary malformation-arteriovenous malformation (CM-AVM) syndrome, hereditary hemorrhagic telangiectasia syndrome, and less commonly, phosphatase and tensin homolog hamartoma tumor syndrome (PHTS). We present a series of three patients with clinically challenging complex AVMs who were found to have underlying PHTS. In all patients, diagnosis was delayed, and the presence of the AVM prompted sampling and genetic testing for PHTS in the absence of other clinical features of the condition. This series highlights the importance of screening for PHTS in the setting of high-flow vascular malformations.

Parental request for familial carrier testing in early childhood: The genetic counseling perspective.

Professional guidelines generally caution against carrier testing in minors, though prior research indicates parents request and providers sometimes facilitate testing for unaffected siblings of a child affected by a genetic disorder. We investigated the perspectives of genetic counselors in North America regarding carrier testing prior to adolescence. Practicing genetic counselors (n = 177) responded to an electronic survey assessing their willingness to facilitate testing in four hypothetical scenarios and their evaluation of parental motivations. Participants did not find parental arguments for testing persuasive, and most were unwilling to facilitate carrier testing in children. A significant interaction effect indicated the presence of nonactionable carrier-associated health risks in adulthood made participants significantly less hesitant when the mode of inheritance was X-linked. Participants considered parental motivations that center the child's interests as significantly more persuasive. This study suggests genetic counselors are resistant to carrier testing for familial disorders in young children and tend to align with current guidelines, yet they recognize nuance in various cases. Further investigation into this topic is warranted to support genetic counselors facing these requests as the ethics of pediatric carrier testing continues to be debated.

Biochemical signatures of disease severity in multiple sulfatase deficiency.

Sulfatases catalyze essential cellular reactions, including degradation of glycosaminoglycans (GAGs). All sulfatases are post-translationally activated by the formylglycine generating enzyme (FGE) which is deficient in multiple sulfatase deficiency (MSD), a neurodegenerative lysosomal storage disease. Historically, patients were presumed to be deficient of all sulfatase activities; however, a more nuanced relationship is emerging. Each sulfatase may differ in their degree of post-translational modification by FGE, which may influence the phenotypic spectrum of MSD. Here, we evaluate if residual sulfatase activity and accumulating GAG patterns distinguish cases from controls and stratify clinical severity groups in MSD. We quantify sulfatase activities and GAG accumulation using three complementary methods in MSD participants. Sulfatases differed greatly in their tolerance of reduction in FGE-mediated activation. Enzymes that degrade heparan sulfate (HS) demonstrated lower residual activities than those that act on other GAGs. Similarly, HS-derived urinary GAG subspecies preferentially accumulated, distinguished cases from controls, and correlated with disease severity. Accumulation patterns of specific sulfatase substrates in MSD provide fundamental insights into sulfatase regulation and will serve as much-needed biomakers for upcoming clinical trials. This work highlights that biomarker investigation of an ultra-rare disease can simultaneously inform our understanding of fundamental biology and advance clinical trial readiness efforts.

Hematopoietic cell transplantation for Mucopolysaccharidosis I in the presence of decreased cardiac function.

BACKGROUND: Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT. METHODS: Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation. RESULTS: Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF. CONCLUSION: Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT.

Disparities in late and lost: Pediatricians' role in following Pompe disease identified by newborn screening.

BACKGROUND AND OBJECTIVES: Pompe disease (PD) results from a deficiency of lysosomal acid α-glucosidase that leads to glycogen accumulation in lysosomes in multiple tissues. There are two phenotypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The objective was to evaluate the diagnostic and follow-up outcomes of children identified with PD through newborn screening (NBS) in the state of Minnesota over a 4-year period. METHODS: This study is a retrospective analysis of infants born in Minnesota between August 1, 2017, and July 31, 2021, by the Minnesota Department of Health NBS Program for Pompe disease. Newborn screening and clinical diagnostic data are summarized for all newborns with positive newborn screens for Pompe disease. RESULTS: Children with IOPD had abnormal biomarkers necessitating immediate initiation of treatment. Children with LOPD are asymptomatic to date (1.25-4.58 years) with normal biomarkers including creatine kinase, urine glucotetrasaccharides, liver function tests, and echocardiogram. The estimated birth prevalence of PD is 1:15,160. The positive predictive value for PD was 81% with a false positive rate of 1.9 per 10 positive screens. 32% of the children with LOPD were lost to follow up among which 66% were from minority ethnic groups. CONCLUSION: This emphasizes the disparity in access to health care among specific demographics, as well as the importance of a primary care provider's early involvement in educating these families. To accomplish this, and ensure equality in follow-up care, the Minnesota Pompe Disease Consortium has been formed.

Phenotype-autosomal recessive osteopetrosis.

Osteopetrosis (OPT) is a life-threatening disease characterized by increased bone mass caused by diminished osteoclast function/differentiation. The autosomal recessive forms, caused by biallelic variants in implicated genes, usually present in infancy. Without treatment, autosomal recessive OPTs are usually fatal within the first 10 years of life [1]. Here, we review the clinical features and associated pathophysiology of the autosomal recessive OPT. A greater understanding of these rare disorders will advance early diagnosis and optimal management.

Early Neonatal Cardiac Phenotype in Hurler Syndrome: Case Report and Literature Review.

Mucopolysaccharidosis type I (MPS I) is a rare inherited lysosomal disorder caused by deficiency of the α-L-iduronidase enzyme, resulting in the progressive accumulation of glycosaminoglycans (GAGs), which interfere with the normal function of multiple tissues and organs. The clinical phenotype includes characteristic facial features, hepatosplenomegaly, dysostosis multiplex, umbilical and inguinal hernias, progressive cognitive deficits with corresponding hydrocephalus, and neuropathology. Untreated children do not survive into the second decade. The common cardiac phenotype seen in MPS I and other MPS types includes valve thickening and dysfunction, conduction abnormalities, coronary artery disease, and cardiomyopathy-usually seen later in the disease course. A 15-month-old ex-35-weeker who presented with cardiomyopathy and left ventricular failure at the age of three weeks is presented here. Early evaluation and diagnosis with the help of newborn screening (NBS), followed by treatment with enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), resulted in improvement of his cardiopulmonary status. In MPS I, an early cardiac phenotype is uncommon. Based on the evidence from the literature review for early neonatal cardiac phenotype, we propose that all infants with abnormal newborn screening for MPS I should receive cardiac screening with echocardiogram and NT-proB-type natriuretic peptide (BNP) during the initial evaluation.

MED12-related Hardikar syndrome: Two additional cases and novel phenotypic features.

Hardikar syndrome (HS) is a MED12-related ultra-rare multiple congenital malformation syndrome known to affect the gastrointestinal, cardiac, and genitourinary systems among other features including cleft lip/palate and pigmentary retinopathy. Only 10 patients affected with HS have been previously described in literature, of which seven were molecularly confirmed. We report a 20-year-old and a 13-month-old patient with HS diagnosed by exome sequencing bringing the total number of clinically diagnosed cases to 12 and MED12 associated to 9. We describe previously unreported molecular and clinical findings associated with HS and review all reported cases to permit prompt diagnosis, appropriate management, and genetic counseling of HS patients.

Rare presentation of FDX2-related disorder and untargeted global metabolomics findings.

We present the case of a 20-year-old male with a history of myopathy and multiple episodes of rhabdomyolysis, and lactic acidosis. He needed hemodialysis for severe rhabdomyolysis-related acute renal failure at the time of initial presentation (age 10 years). Exome sequencing detected a homozygous likely pathogenic variant in FDX2 (c.12G>T, p.M4I). The FDX2 gene encodes a mitochondrial protein, ferredoxin 2, that is involved in the biogenesis of Fe-S clusters. Biallelic pathogenic variants in FDX2 have previously been associated with episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy. Only two cases with FDX2-related rhabdomyolysis as a predominant feature have been reported in medical literature. Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis. He does not have optic atrophy or leukoencephalopathy. This is the oldest patient reported with FDX2-related disorder and he has significantly elevated CK during episodes of rhabdomyolysis. In addition, we describe untargeted global metabolomic findings during an episode of metabolic decompensation, shedding light on the biochemical pathway perturbation associated with this ultra-rare genetic disorder.

Gastrointestinal Dysmotility Is a Significant Feature in 2 Siblings With a Novel Inositol 1,4,5-Triphosphate Receptor 1 (ITPR1) Missense Variant.

We present 2 siblings with a novel type 1 inositol 1,4,5-triphosphate receptor (ITPR1) missense variant who exhibit gastrointestinal dysmotility (chronic constipation and gastroparesis). ITPR1 is expressed in the cerebellum and interstitial cells of Cajal. Periodic release of calcium by ITPR1 initiates pacemaker currents, resulting in smooth muscle contraction. ITPR1 mutations are known to be associated with neurologic syndromes, and these variants have not previously been associated with significant gastrointestinal manifestations in humans. Using whole-genome sequencing, in silico prediction software, biopsy samples, and manometry, the identified novel ITPR1 variant is likely pathogenic and may have neurogastroenterology implications.

Cobalamin J disease detected on newborn screening: Novel variant and normal neurodevelopmental course.

Cobalamin J disease (CblJ) is an ultra-rare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic acidemia and homocystinuria. It is caused by pathogenic variants in ABCD4, which encodes an ATP-binding cassette (ABC) transporter that affects the lysosomal release of cobalamin (Cbl) into the cytoplasm. Only six cases of CblJ have been reported in the literature. Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and hematological abnormalities. Information on clinical outcomes is extremely limited, and no cases of presymptomatic diagnosis have been reported. We describe a now 17-month-old male with CblJ detected by newborn screening and confirmed by biochemical, molecular, and complementation studies. With early detection and initiation of treatment, this patient has remained asymptomatic with normal growth parameters and neurodevelopmental function. To the best of our knowledge, this report represents the first asymptomatic and neurotypical patient with CblJ.

Hematologic presentation and the role of untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency.

Riboflavin transporter deficiency (RTD) (MIM #614707) is a neurogenetic disorder with its most common manifestations including sensorineural hearing loss, peripheral neuropathy, respiratory insufficiency, and bulbar palsy. Here, we present a 2-year-old boy whose initial presentation was severe macrocytic anemia necessitating multiple blood transfusions and intermittent neutropenia; he subsequently developed ataxia and dysarthria. Trio-exome sequencing detected compound heterozygous variants in SLC52A2 that were classified as pathogenic and a variant of uncertain significance. Bone marrow evaluation demonstrated megaloblastic changes. Notably, his anemia and neutropenia resolved after treatment with oral riboflavin, thus expanding the clinical phenotype of this disorder. We reiterate the importance of starting riboflavin supplementation in a young child who presents with macrocytic anemia and neurological features while awaiting biochemical and genetic work up. We detected multiple biochemical abnormalities with the help of untargeted metabolomics analysis associated with abnormal flavin adenine nucleotide function which normalized after treatment, emphasizing the reversible pathomechanisms involved in this disorder. The utility of untargeted metabolomics analysis to monitor the effects of riboflavin supplementation in RTD has not been previously reported.

Liver transplantation in propionic and methylmalonic acidemia: A single center study with literature review.

BACKGROUND: Organic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data. STUDY DESIGN/METHODS: We performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected. RESULTS: The median age of transplantation for subjects with MMA was 7.2 years with a median follow up of 4.3 years. The median age of transplantation for subjects with PA was 1.9 years with a median follow up of 5.4 years. The survival rate at 1 year and 5 years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT. CONCLUSION: In a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.

Loss of CLTRN function produces a neuropsychiatric disorder and a biochemical phenotype that mimics Hartnup disease.

Hartnup disease is an autosomal recessive condition characterized by neutral aminoaciduria and behavioral problems. It is caused by a loss of B0 AT1, a neutral amino acid transporter in the kidney and intestine. CLTRN encodes the protein collectrin that functions in the transportation and activation of B0 AT1 in the renal apical brush bordered epithelium. Collectrin deficient mice have severe aminoaciduria. However, the phenotype associated with collectrin deficiency in humans has not been reported. Here we report two patients, an 11-year-old male who is hemizygous for a small, interstitial deletion on Xp22.2 that encompasses CLTRN and a 22-year-old male with a deletion spanning exons 1 to 3 of CLTRN. Both of them present with neuropsychiatric phenotypes including autistic features, anxiety, depression, compulsions, and motor tics, as well as neutral aminoaciduria leading to a clinical diagnosis of Hartnup disease and treatment with niacin supplementation. Plasma amino acids were normal in both patients. One patient had low 5-hydroxyindoleacetic acid levels, a serotoninergic metabolite. We explored the expression of collectrin in the murine brain and found it to be particularly abundant in the hippocampus, brainstem, and cerebellum. We propose that collectrin deficiency in humans can be associated with aminoaciduria and a clinical picture similar to that seen in Hartnup disease. Further studies are needed to explore the role of collectrin deficiency in the neurological phenotypes.

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures.

Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia. COX4I1 encodes subunit 4, isoform 1 of cytochrome c oxidase. Cytochrome c oxidase is a respiratory chain enzyme that plays an important role in mitochondrial electron transport and reduces molecular oxygen to water leading to the formation of ATP. Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome. Here, we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh-syndrome, and a novel homozygous variant on COX4I1, expanding the known clinical phenotype associated with pathogenic variants in COX4I1.

Novel deletion of 6p21.31p21.1 associated with laryngeal cleft, developmental delay, dysmorphic features and vascular anomaly.

Interstitial deletions involving chromosome region 6p21.31p21.2 have not been previously reported in the literature. Here, we present a 2 year old girl with global developmental delay, severe speech delay, dysmorphic features, laryngeal cleft, anterior descending aorta that occluded the left main bronchus and a novel de novo deletion of chromosome 6: arr[hg19] 6p21.31p21.2 (35462950-36725083)x1. The deletion, which was diagnosed by array comparative genomic hybridization and further confirmed with fluorescence in situ hybridization, was approximately 1.26 Mb and contained 28 RefSeq genes. The deleted region includes 24 protein coding genes and 4 non-coding genes. This represents a novel microdeletion that has not been previously reported in the literature.