Elisa Cattaneo

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by mutations in the ABCD1 gene. Early diagnosis is critical to manage adrenal insufficiency and cerebral forms of the disease. Since 2021, a pilot newborn screening (NBS) program for X-ALD has been launched in Lombardy, Italy. From September 2021 to June 2025, 138,116 newborns (≥37 weeks’ gestational age) were screened for elevated C26:0-lysophosphatidylcholine (C26:0-LPC) levels using a two-tier algorithm. Genetic testing was performed in non-negative cases. Males found to be ABCD1 variant carriers were enrolled in multidisciplinary follow-up, including neurological, endocrinological, and nutritional assessments. Eleven individuals (six males, five females) carried pathogenic or likely pathogenic ABCD1 variants. Three males were diagnosed with adrenal insufficiency and started hydrocortisone therapy between 1 and 2 years of age. Growth parameters were within normal range overall, but two children showed signs of stunting associated with poor dietary compliance. Additionally, three patients were diagnosed with Zellweger spectrum disorders (ZSDs). No patients affected with Aicardi-Goutières Syndrome were identified. Newborn screening for X-ALD in Italy is feasible and enables early detection and intervention. Biochemical markers and genetic analysis are reliable tools for identifying affected males and female carriers. Multidisciplinary management is essential to address medical and psychosocial challenges during follow-up.

Background: Ebstein’s anomaly (EA) is a rare congenital heart defect characterized by failure of tricuspid valve delamination during embryogenesis. Left ventricular (LV) hypertrabeculation results from incomplete myocardial compaction during fetal development. EA is associated with LV hypertrabeculation in 0.14% of cases, and EA is the most common congenital heart disease in LV hypertrabeculation (up to 29%), suggesting a shared embryogenetic pathway. Case Report: We describe a female patient prenatally diagnosed with EA and a large ventricular septal defect. Postnatal echocardiography confirmed EA with moderate regurgitation and revealed previously unnoticed left ventricular excessive trabeculations. Whole exome sequencing revealed a heterozygous never-described variant of unknown significance in the TNNC1 gene. Discussion: The genetic link between EA and LV hypertrabeculation remains unclear, though variants in sarcomeric or cytoskeletal genes like MYH7, TPM1, and NKX2.5—essential for cardiac development—have been implicated. A developmental hypothesis suggests that aberrant contraction during endocardial-to-mesenchymal and epicardial-to-mesenchymal transformation (5th–8th gestational weeks) may affect valve delamination and ventricular compaction via parallel signaling pathways. TNNC1 encodes troponin C1, a subunit of the troponin complex involved in muscle contraction. Its mutations are known to alter calcium sensitivity and impair cardiac contractility. Conclusions: EA and LV hypertrabeculation patients diagnosed in infancy have a greater risk of negative outcomes. Early, especially prenatal, diagnosis is crucial. Genetic analysis can provide fundamental insight into cardiac development. This new and rare variant of TNNC1 gene supports the hypothesis that early cardiomyocytes dysfunction disrupts both valve delamination and left ventricular compaction and that the two diseases share a common genetic pathway related to cardiomyocyte contraction.

We described new forms of thyroglobulin gene (TG) mutation resulting in fetal goiter and congenital hypothyroidism in a pendred syndrome (PS) patient. Fetal hypothyroidism was diagnosed, based on ultrasonographic evidence of goiter alongside with fetal blood measurement of TSH (>100 mIU/L); levothyroxine intrauterine treatment was performed. At birth, ultrasound thyroid enlargement and primary hypothyroidism were confirmed. On Day 11, hearing screening using a combination of otoacoustic emissions and auditory brainstem response revealed profound bilateral sensorineural deafness. Genetic analysis revealed TG variants [c.727C>T,p.(Àrg243Trp) and c.67l8G>T,p.(Glu2240Stop) in heterozygosis. Mutation c.164+1delG,p.(Ser55Ilefs   ^∗ 11) in homozygosis of the SLC26A4 gene was also detected. The extension of the analysis to the patient’s parents revealed the presence of the heterozygous variant in the SLC26A4 gene [c.164+1delG] and in the TG gene [c.727C>T] in the father, and the heterozygous variant in the SLC26A4 gene [c.164+1delG] and in the TG gene [c.6718G>T] in the mother. This is the first report associating mutations in TG with a PS patient. The combination of genetic factors likely contributed to the patient’s clinical conditions, which included fetal goiter with CH and profound bilateral hearing loss, representing a rare instance of mutations linked to inherited thyroid disorders.

KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 (ANKRD11) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11. A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.

Autosomal dominant hypophosphatemic rickets (ADHR) is an extremely rare form of genetic rickets caused by mutations in the fibroblast growth factor 23 gene. ADHR is characterized by hypophosphatemia secondary to isolated renal phosphate wasting. Only a few cases of ADHR have been reported in the literature to date. We describe the case of a 17-month-old girl who presented with severe failure to thrive (length: −4.08 standard deviation (SD), weight: −2.2 SD) and hypotonia. Hypophosphatemia, decreased tubular phosphate reabsorption (69%), and rachitic lesions were found. Genetic analysis showed the heterozygous variant c.536G>A (NM_020638.3:c.536G>A) in exon 3 of the FGF23 gene, leading to the diagnosis of ADHR. She was treated with phosphate salts and oral alfacalcidol. After 4 years of treatment, at 5 years of age, the patient’s ADHR resolved spontaneously. Considering the lack of knowledge regarding ADHR, we reviewed the literature to describe the features of this rare and poorly understood disease. Eleven ADHR pediatric cases have been described thus far, with cases tending to be more common in females than males. Similar to the general population, two groups of patients with ADHR can be described depending on the mutations present: patients with an R179 and R176 mutation have early-onset of disease and higher frequency of rickets, and a milder and late-onset of disease, respectively. Symptoms and disease severity may fluctuate. Spontaneous remission may occur during the pediatric age.

The term PROS (PIK3CA-Related Overgrowth Spectrum) indicates a wide spectrum of overgrowth disorders related to somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) pathway. We present three cases with PIK3CA mutation and clinical characteristics encompassing MCAP (megalencephaly-capillary malformation) condition but lacking all criteria to a certain diagnosis, most of all showing prevalent and peculiar involvement of cerebellar structures at MRI (magnetic resonance imaging) mainly consisting in cortical rim thickening and abnormal orientation of folia axis. These cases expand the spectrum of intracranial MRI features in PIK3CA disorders.

Osteopathia striata with cranial sclerosis (OSCS, OMIM#300373) is an X-linked dominant sclerosing bone dysplasia that shows a distinct phenotype in females and males. In 2009, Zandra Jenkins et al found that germline mutations in the FAM123B/WTX/AMER1 gene, mapped to chromosome Xq11.2, cause both the familial and sporadic forms of OSCS. Intriguingly, the WTX gene was already known as a putative tumor suppressor gene, since in 2007 Rivera et al had reported inactivating WTX mutations in Wilms’ tumor (WT), the most frequent renal tumor of childhood. Here we review the heterogeneous clinical presentation of OSCS patients and the involvement of WTX anomalies in OSCS and in WT.