Dyshormonogenesis accounts for 15%–20% of permanent congenital hypothyroidism (CH), and pathogenic variants in the thyroid peroxidase (TPO) gene are its most frequent cause. We report three brothers, all diagnosed with severe CH in the neonatal period and referred to our Medical Genetics Unit in 2021 for molecular characterization and genetic counseling. Whole‐exome sequencing, followed by a targeted thyroid gene panel, identified the same compound heterozygous TPO genotype in all three: NM_000547.6:c.1297G > A, p.(Val433Met), inherited from the carrier mother, and NM_000547.6:c.1964G > C, p.(Cys655Ser), inherited from the carrier father, confirming autosomal recessive dyshormonogenetic CH. At neonatal diagnosis, initial TSH exceeded 100 mIU/L in all three brothers (reference range approximately 1–20 mIU/L beyond the first days of life (Wassner 2018 and Léger et al. 2014)). Despite this identical genetic cause and comparable neonatal severity, the three brothers (hereafter Patient 1, Patient 2, and Patient 3, the index case) went on to show markedly divergent clinical trajectories. Patient 1 was treated continuously from birth. Patient 2 was correctly identified neonatally through a proactive family thyroid screening, prompted by his elder brother’s pre‐existing diagnosis, but was then lost to adequate endocrine follow‐up: his levothyroxine dose stayed static and unadjusted for several years while his TSH remained persistently elevated. Patient 3, the index case, was diagnosed at Day 3 through Guthrie neonatal screening, and it was his diagnosis that prompted the family‐wide reassessment which ultimately confirmed the genotype in all three brothers. He additionally carries a heterozygous SLC26A4 variant of uncertain significance. Together, these three cases show that the prognosis of treated neonatal CH depends as much on the quality of postdiagnosis monitoring as on how quickly the initial diagnosis is made. They also make the case for systematic family thyroid screening once a sibling is known to carry dyshormonogenetic CH, and for the value molecular diagnosis adds to parental counseling and reproductive planning.
Background 3q29 deletion syndrome (MIM #609425) is a rare genomic disorder characterized by variable expressivity and incomplete penetrance. Somatic mosaicism for a 3q29 deletion in an affected proband has rarely been documented. Mosaicism inferred from attenuation of the array signal requires confirmation by an independent method. When a chromosomal deletion encompasses an autosomal recessive (AR) disease gene, evaluation of the second allele may be informative. Extreme food selectivity associated with autism spectrum disorder (ASD) poses substantial but underrecognized nutritional risk. Case Presentation An 8‐year‐old Japanese boy with ASD, intellectual disability, absent speech, progressive obesity, hepatosplenomegaly, and congenital toe syndactyly underwent chromosomal microarray analysis (CMA). A 1.27‐Mb interval at 3q29 (arr[GRCh37] chr3:195,804,728–197,074,949) was segmented with a mean log2 ratio of −0.252 across 59 informative probes, against an excellent array quality (derivative log ratio spread 0.179). The signal returned to baseline immediately outside the interval. The magnitude of the attenuation is intermediate between a normal diploid state and that expected for a constitutional heterozygous deletion and is compatible with a suspected mosaic deletion; the laboratory’s automated nomenclature nevertheless assigned a copy number of 2, with the explicit caveat that copy number was not verified, and no independent confirmatory method was applied. The interval is atypical and nested within the recurrent 3q29 region and encompasses TFRC , RNF168 , PAK2 , and DLG1 . A targeted 15‐gene DNA repair panel identified no pathogenic or likely pathogenic variant on the second RNF168 allele. An incidental heterozygous NBN variant of uncertain significance (c.265A > G, p.Ile89Val; NM_002485.5) was nondiagnostic and did not alter management. Neither exome nor genome sequencing was available as a reimbursed clinical investigation, and parental samples were not obtained. Microcytosis and hypochromia were present at both time points; serum iron was within the reference interval at baseline and low at follow‐up, ferritin remained within the reference interval throughout, and no threshold‐based criterion for iron deficiency was met. Low 25‐hydroxyvitamin D, low vitamin C, and low retinol‐binding protein were documented at two time points and considered most likely related to the markedly restricted diet. Plasma amino acids; serum carnitine fractions; zinc; selenium; vitamins B1, B2, and B12; immunoglobulins; and alpha‐fetoprotein were unremarkable; serum copper was elevated in the presence of a raised C‐reactive protein, and ceruloplasmin was not measured. The cause of the hepatosplenomegaly remained unresolved. Conclusion An attenuated CMA signal at 3q29, compatible with a suspected mosaic deletion but not independently confirmed, was identified in a patient whose phenotype overlaps 3q29 deletion syndrome. Where a deletion encompasses an AR disease gene whose phenotype overlaps the presentation, second‐allele evaluation may add diagnostic resolution. This case highlights the importance of considering nutritional assessment in children with ASD and extreme food selectivity; the biochemical abnormalities persisted at follow‐up, although no vitamin D had been administered before the follow‐up sample and treatment exposure and adherence were not systematically documented.
Introduction Hyperphosphatasia with intellectual disability syndrome (HPMRS), also known as Mabry syndrome, is a rare autosomal recessive disorder of glycosylphosphatidylinositol (GPI) anchor biosynthesis. Approximately 20 cases with pathogenic PIGO variants have been reported worldwide. This makes PIGO ‐related HPMRS one of the rarest molecularly defined subtypes of the disease. Case Report We report a male infant from French Guiana. He presented with neonatal tremors, global developmental delay with postural delay, and generalized tonic–clonic seizures with dystonic features. Symptoms began at 9 months and worsened by 13 months. Biochemical testing showed persistently elevated serum alkaline phosphatase (ALP 477 then 415 U/L; reference range 142–335 U/L). Trio whole‐exome sequencing identified two compound heterozygous PIGO variants: c.839T > C (p.Met280Thr), inherited from the father, and c.590C > T (p.Pro197Leu), inherited from the mother. The diagnostic laboratory classified both as probably pathogenic (Class 4). Physical examination at 17 months showed growth retardation (height and weight at −2 SD) and a reducible umbilical hernia. There was no notable facial dysmorphism or limb anomaly. Conclusion We report the first molecularly characterized case of PIGO ‐related HPMRS in French Guiana. The diagnosis combined clinical, biochemical, and molecular evaluation. This case shows that the PIGO phenotype extends beyond classic dysmorphic presentations.
Focal segmental glomerulosclerosis (FSGS) is a common histopathological diagnosis among adult patients presenting with nephrotic syndrome. This pattern is associated with diverse underlying pathophysiological mechanisms, which may influence disease management, therapeutic response, and prognosis. Genetic forms of FSGS are caused by variants in genes encoding proteins expressed in podocytes or the glomerular basement membrane. Multiple genes have been implicated in the pathogenesis of genetic FSGS, and clinical presentation can vary depending on the specific gene involved. We report the case of a young man with nephrotic syndrome and a histopathological diagnosis of FSGS, in whom genetic testing identified a novel LAMA5 c.6940C > T p.(Arg2314Trp) variant in a consanguineous Saudi family, consistent with autosomal recessive inheritance. Family genetic analysis revealed that the proband’s mother and two siblings are homozygous for the identified variant, whereas his father and the remaining two siblings are heterozygous. The variant is currently classified as a variant of uncertain significance (VUS). This report characterizes the associated clinical phenotype and discusses the findings of family segregation analysis in the context of variable expressivity and incomplete penetrance.
Background Nonmosaic Trisomy 9 is a rare chromosomal abnormality, accounting for approximately 2.2%–2.7% of spontaneous abortions caused by autosomal trisomies, and is characterized by a heterogeneous multisystem phenotype and an extremely poor prognosis. Prenatal imaging may demonstrate severe multisystem abnormalities; however, these findings are not specific to Trisomy 9, making cytogenetic testing essential for definitive diagnosis. We report a case of prenatally diagnosed apparently nonmosaic Trisomy 9 in which diagnosis enabled individualized perinatal care. Case A 44‐year‐old multiparous woman was referred to our hospital at 25 weeks’ gestation because of severe fetal growth restriction and multiple structural anomalies. Amniocentesis at 28 weeks’ gestation demonstrated 47,XY,+9 in all 100 examined colonies, consistent with apparently nonmosaic Trisomy 9. Following multidisciplinary counseling and shared decision‐making, an individualized birth plan was developed. The family wished to avoid aggressive life‐prolonging interventions while prioritizing the opportunity to meet their infant alive; therefore, fetal monitoring, cesarean delivery for fetal indications, and mask ventilation without further resuscitation were incorporated into the plan. Emergency cesarean delivery was performed at 36 weeks and 2 days for nonreassuring fetal status. The infant died approximately 9 h after birth while receiving family‐centered palliative care. Conclusion This case highlights the clinical importance of definitive prenatal cytogenetic diagnosis in apparently nonmosaic Trisomy 9, enabling phenotype‐informed prognostic counseling and individualized perinatal management.
