Recognizing Lipofuscinosis as a Guide in Antiepileptic Treatment: Clinical Description of the First Mexican Case With Neuronal Ceroid Lipofuscinosis Type 7 (NCL7).

Neuronal ceroid lipofuscinosis type 7 (NCL7) is a rare form of childhood dementia; it is part of a group of diseases characterized by rapid progressive cognitive decline, blindness associated with retinitis pigmentosa, and seizures. We report the clinical and molecular characteristics of the first Mexican patient with NCL7, highlighting a particularly atypical disease course. The typical presentation form is expected to have reduced life expectancy and an average age of ambulation loss at 12 years. Our 27-year-old patient retains the ability to walk. The patient's unique presentation could, in part, be attributed to her genetic profile: a hypomorphic allele carrying a missense variant (c.1390G>A) and an almost null allele with a frameshift variant (c.1086del), contributing to the preservation of some protein function. Throughout her childhood and early adulthood, our patient experienced a variable response to antiseizure drugs, attributed to a lack of recognition of the disease and the specific efficacy of certain antiseizure medications. Our findings underscore the significance of considering this genetic condition and acknowledging its clinical heterogeneity.

Genotype and phenotype characterization of primary hypertrophic osteoarthropathy type 2 and chronic enteropathy associated with SLCO2A1: Report of two cases and literature review.

Autosomal recessive type 2 primary hypertrophic osteoarthropathy (PHOAR2) and chronic enteropathy associated with SLCO2A1 (CEAS) are two entities caused by pathogenic variants (PVs) in the SLCO2A1 gene that can coexist or occur independently from one another. We report two cases of PHOAR2 in Mexico with concomitant CEAS and conducted a review of the literature of the reported cases of PHOAR2 and/or CEAS to analyze the relationship between their genotype and phenotype presentation. The patients from our Institution with classical PHOAR2 phenotype and CEAS, harbored SLCO2A1 c.547G > A and c.1768del variants. We reviewed 232 cases, of which 86.6% were of Asian origin, and identified 109 different variants in SLCO2A1. Intron 7, exon 13, and exon 4 were predominantly affected. The two most common PVs were c.940 + 1G > A and c.1807C > T. We found a statistically significant association between SLCO2A1 variants located in intron 7, exons 12, and 13 and the development of CEAS. Missense variants were more frequent in isolated PHOAR2, while a greater proportion of protein-truncating variants (PTVs) were found in CEAS. Further investigation is imperative to elucidate the underlying pathophysiological mechanisms associated with CEAS, thereby facilitating the identification of effective therapeutic interventions.

Vitamin D Hydroxylation-deficient Rickets Type 1A Misdiagnosed as Normocalcemic Primary Hyperparathyroidism.

Vitamin D hydroxylation-deficient rickets type 1A is an autosomal recessive disorder caused by pathogenic variants in CYP27B1 gene, which encodes for 1α-hydroxylase, the enzyme responsible for the conversion of 25-OH vitamin D into its active form 1,25(OH)2 vitamin D. We report the case of a 3-year-old female Mexican patient with growth retardation and progressive bone deformity, whose laboratory studies showed 25-OH vitamin D deficiency, a normal serum calcium and an elevated intact parathyroid hormone level that remained high despite calcitriol, cholecalciferol, and calcium supplementation. 99mTc sestamibi gammagram showed findings suggestive of parathyroid hyperplasia. Bone histomorphometry showed an image consistent with hyperparathyroidism without findings of osteomalacia, so normocalcemic primary hyperparathyroidism was suspected and a subtotal parathyroidectomy was performed, with the patient developing postoperative hypoparathyroidism. When she arrived at our clinic at age 18 years, she showed calcium- and calcitriol-dependent hypocalcemia, with secondary hyperparathyroidism and low levels of 1,25(OH)2 vitamin D in the absence of a 25-OH vitamin D deficiency, reflecting a defect in 1α-hydroxylation. Molecular testing revealed compound heterozygous variants in CYP27B1 gene. This is the first reported case of an inherited disorder of vitamin D metabolism that was diagnosed and surgically treated as primary hyperparathyroidism.

Esophageal stenosis in an adult Mexican patient with diastrophic dysplasia: Case report.

Diastrophic dysplasia (DTD) is caused by biallelic pathogenic variants in the SLC26A2 gene. We report the case of a 49-year-old female with DTD and esophageal stenosis. This broadens the phenotypic spectrum in adult patients with DTD and raises awareness of extra-skeletal manifestations that could develop in later stages of life.

Hypertrophic cardiomyopathy in an adult patient with Noonan syndrome with multiple lentigines.

Noonan syndrome with multiple lentigines (NSML) is a rare RASopathy caused by pathogenic variants (PV) predominantly in PTPN11 gene. We report a 54-year-old male with apical hypertrophic cardiomyopathy, who was diagnosed with NSML due to his short stature, multiple lentigines, winged neck, pectus excavatum, and a heterozygous PV in PTPN11 c.836A > ¡G.

Severe Congenital Neutropenia Type 4: A Rare Disease Harboring a G6pc3 Gene Pathogenic Variant Particular to the Mexican Population.

Background: Severe congenital neutropenia type 4 (SCN4) is a rare autosomal recessive granulopoiesis disorder caused by G6PC3 gene pathogenic variants. The estimated prevalence is 1/10,000,000 people. Over 90% of patients present a syndromic form with variable multisystemic involvement, including congenital heart defects, increased visibility of superficial veins (IVSV), inflammatory bowel disease, and congenital urogenital defects as prominent symptoms. Objectives: The objective of the study was to study non-hematological phenotypic findings that suggest a clinical diagnosis of SCN4. Methods: We examined medical records of patients diagnosed with neutropenia from January 2000 to December 2020, selecting cases with non-hematologic manifestations for phenotypic description and G6PC3 gene sequencing. Results: We found 11 cases with non-hematologic features: congenital heart defects in 8, IVSV in 6, inflammatory bowel disease in 4, urogenital defects in 4, and similar facial appearance. In addition, Sanger sequencing confirmed 3 homozygous cases for the c.210delC variant, a compound heterozygous harboring this variant, and a c.199_218+1 deletion. Conclusions: Our findings of the c.210delC variant in very close geographical settings, to date, have only been reported among Mexicans, and a mutual uncommon surname in two families strongly supports a founder effect for the variant in the studied population. Furthermore, the described non-hematologic symptoms in patients with severe primary neutropenia should be explored, confirming SCN4 by investigating G6PC3 gene mutations.

Severe Congenital Neutropenia Type 4: A Rare Disease Harboring a G6pc3 Gene Pathogenic Variant Particular to the Mexican Population

ABSTRACT Background: Severe congenital neutropenia type 4 (SCN4) is a rare autosomal recessive granulopoiesis disorder caused by G6PC3 gene pathogenic variants. The estimated prevalence is 1/10,000,000 people. Over 90% of patients present a syndromic form with variable multisystemic involvement, including congenital heart defects, increased visibility of superficial veins (IVSV), inflammatory bowel disease, and congenital urogenital defects as prominent symptoms. Objectives: The objective of the study was to study non-hematological phenotypic findings that suggest a clinical diagnosis of SCN4. Methods: We examined medical records of patients diagnosed with neutropenia from January 2000 to December 2020, selecting cases with non-hematologic manifestations for phenotypic description and G6PC3 gene sequencing. Results: We found 11 cases with non-hematologic features: congenital heart defects in 8, IVSV in 6, inflammatory bowel disease in 4, urogenital defects in 4, and similar facial appearance. In addition, Sanger sequencing confirmed 3 homozygous cases for the c.210delC variant, a compound heterozygous harboring this variant, and a c.199_218+1 deletion. Conclusions: Our findings of the c.210delC variant in very close geographical settings, to date, have only been reported among Mexicans, and a mutual uncommon surname in two families strongly supports a founder effect for the variant in the studied population. Furthermore, the described non-hematologic symptoms in patients with severe primary neutropenia should be explored, confirming SCN4 by investigating G6PC3 gene mutations.