Citrullinemia type 1: genetic diagnosis and prenatal diagnosis in subsequent pregnancy

Citrullinemia type 1 was diagnosed by tandem mass spectrometry in a full term male neonate who presented with an acute catastrophic collapse on the 3rd day of life. Both parents were identified to be carriers for the exon 15 p Gly390Arg mutation in the argininosuccinate synthetase gene located at chromosome 9q34.1. Chorionic villus sampling and prenatal genetic testing in the subsequent pregnancy revealed an affected fetus resulting in termination of pregnancy

Ptosis as a unique hallmark for autosomal recessive WNT1-associated osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, mainly characterized by bone fragility and low bone mass. Defects in the type I procollagen-encoding genes account for the majority of OI, but increasingly more rare autosomal recessive (AR) forms are being identified, which are caused by defects in genes involved in collagen metabolism, bone mineralization, or osteoblast differentiation. Bi-allelic mutations in WNT1 have been associated with a rare form of AR OI, characterized by severe osteoporosis, vertebral compression, scoliosis, fractures, short stature, and variable neurological problems. Heterozygous WNT1 mutations have been linked to autosomal dominant early-onset osteoporosis. In this study, we describe the clinical and molecular findings in 10 new patients with AR WNT1-related OI. Thorough revision of the clinical symptoms of these 10 novel patients and previously published AR WNT1 OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype

Bain type of X‐linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA binding proteins, which aid in maturation, stabilization, and transport of mRNA. They have a significant role in cellular nucleic acid metabolism. The hnRNPs alter gene expression and are linked to various neurodegenerative disorders and cancers. Previously, six unrelated girls with developmental delay, intellectual disability, and hypotonia were found to have de novo heterozygous pathogenic missense variants in HNRNPH2, located on the X chromosome. A gain‐of‐function effect was proposed for the variant and it was thought to be lethal in males as no surviving males were identified. We describe a family with two affected siblings, one male and one female, with a known pathogenic variant in HNRNPH2, possibly due to maternal germline mosaicism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152580/1/ajmga61388.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152580/2/ajmga61388_am.pd

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Child Care for Families Leaving Temporary Assistance for Needy Families

Since Temporary Assistance for Needy Families (TANF) replaced the Aid to Families with Dependent Children program in 1996, the welfare rolls have decreased by more than 40 percent. While unemployment and poverty rates have declined, families who leave welfare generally earn low wages and remain below the poverty level. Because families leaving welfare are mostly single mothers with young children, child care is critical to their ability to work outside the home. Low-income parents trying to make ends meet, as well as employers of low-wage workers, emphasize the importance of appropriate, affordable child care in enabling women who leave welfare to make a successful transition into the work force. However, lack of adequate child care and the high cost of child care often force working parents leaving welfare to make the impossible choice between providing inadequate care for their children and failing to provide for their families financially. While child care subsidies can help low-income parents, many families do not use child care subsidies for which they are eligible. Although subsidies can help poor families, they do not necessarily solve problems of affordability or availability of good child care choices. Low-income families also are likely to face one or more special issues that make finding appropriate child care even more difficult. In this article the authors discuss child care subsidies for families leaving welfare, key issues low-income working families face in accessing quality, affordable child care, and advocacy strategies to help ensure that state child care policies serve these families effectively

Is Estimation of HbA2 Alone Sufficient for Screening Beta Thalassaemia Carriers: A Case in Perspective

Beta thalassaemia is one of the most common inherited haemoglobinopathies, characterised by reduced or absent production of the beta globin chain. In India, the carrier frequency of thalassaemia is estimated to be 3-4%. The prevention of Beta thalassaemia is the best strategy, and this can be achieved through carrier screening and prenatal diagnosis. Carriers of beta thalassaemia can be easily identified using haematological parameters such as complete blood count and High Performance Liquid Chromatography (HPLC) for haemoglobin analysis. The characteristic findings observed in thalassaemia carriers include microcytosis, hypochromia, with a Mean Corpuscular Volume (MCV) of less than 80 fL and Mean Corpuscular Haemoglobin (MCH) of less than 28 pg. They also present with elevated levels of HBA2 (α2δ2) ≥3.5%. Carrier screening for beta thalassaemia primarily relies on the observation of elevated HbA2 levels. However, in rare cases, some carriers can have normal HbA2 levels, leading to false-negative screening results. In a case involving a married couple who underwent routine preconceptional screening by complete blood count and HPLC for thalassaemia screening, the male partner had elevated HbA2 levels (5.2%), while the female partner had normal HbA2 levels (1.6%). Molecular testing revealed that the male partner was heterozygous for the Intervening Sequence (IVS) 1-5 (G>C) mutation, while the female partner was found to be heterozygous for the CD41-42 (-CTTT) mutation. It is important to consider molecular testing of the HBB gene in couples, even if one partner is a carrier and the other partner has normal or borderline HbA2 levels