Autosomal Dominant Transmission Research Articles

Prevalence of Brugada ECG pattern in psychiatric patients: a longitudinal prospective cohort of 550 patients

Abstract Background Brugada syndrome (BrS) is an inherited disorder with autosomal dominant transmission, which occurs predominantly in males in the third to fourth decade of life with resting syncope, nocturnal agonic breathing, major ventricular arrhythmias and sudden death. Arrhythmic complications can occur spontaneously or following exposure to triggers such as fever, or certain categories of medications, including psychiatric drugs. Aim of the study To evaluate the prevalence of Brugada ECG pattern in psychiatric patients. Methods from January 2023 to Decembre 2023, 550 consecutive patients who were admitted to the psychiatric department of our university hospital were enrolled. For each patient, electrocardiographic and anamnestic data including psychiatric diagnosis, current drug therapy and family history were collected. Results Twenty-one out of five-hundred and fifty patients (3.8%) presented with a Brugada ECG pattern. Mean age was 42±6 years and seventeen out of twenty-one patients (81%) were male. Two patients exhibited a Spontaneous type 1 Brugada ECG pattern meanwhile nineteen patients had a Brugada type 2 or 3 ECG pattern. When compared to the general population, those with Brugada ECG had longer P wave duration (110±7 vs 103±13 msec p<0.01) and longer QRS duration (97±14 vs 89±12 msec p=0.04). Evaluating psychiatric disorders, patients with Brugada ECG had high prevalence of mood disorders (10 out of 21, 47%). Other disorders were schizophrenia (3 out of 21, 14%), cognitive retardation (5 out of 21, 23%), and attention disorder (1 out of 21, 5%). Moreover 4 patients were drug addicted. Only 5 out of 21 (24%) patients had a family history of psychiatric and neurological disorders. Conclusions Brugada ECG pattern has a prevalence of 3.8% in a large cohort of psychiatric patients. Mood disorders was the most common diagnosis in this cohort. Large prospective registries are needed to evaluate the clinical feature and potential clinical implication of this findings.

Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing.

Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development.

Emphasis on Early Prenatal Diagnosis and Perinatal Outcomes Analysis of Apert Syndrome.

Apert syndrome is an inherited condition with autosomal dominant transmission. It is also known as acrocephalosyndactyly type I, being characterized by a syndrome of craniosynostosis with abnormal head shape, facial anomalies (median hypoplasia), and limb deformities (syndactyly, rhizomelic shortening). The association can suspect the prenatal diagnosis of these types of anomalies. The methodology consisted of revising the literature, by searching the PubMed/Medline database in which 27 articles were selected and analyzed, comprising 32 cases regarding the prenatal diagnosis of Apert syndrome. A series of ultrasound parameters, the anatomopathological abnormalities found, the obstetric results, and the genetic tests were followed. The distribution of imaging results (US, MRI) identified in the analyzed cases was as follows: skull-shaped abnormalities were evident in 96.8% of cases, facial abnormalities (hypertelorism 43.7%, midface hypoplasia 25%, proptosis 21.8%), syndactyly in 87.5%, and cardiovascular abnormalities in 9.3%. The anomalies detected by the ultrasound examination of the fetus were confirmed postnatally by clinical or gross evaluation or imaging. The management of these cases requires an early diagnosis, an evaluation of the severity of the cases, and appropriate parental counseling.

The first case report on maturity-onset diabetes of young-11 from West Bengal, India

Maturity-onset diabetes of young (MODY) is a clinically group of heterogeneous disorder characterized by non-insulin-dependent diabetes diagnosed at a young age (<25 years) with autosomal dominant transmission and lack of autoantibodies. This case report is on MODY in a 30-day-old baby. The patient also has an umbilical hernia and choledochal cyst. We present an instance of 30-day-old child with MODY with a family background of diabetes. While more data are needed to justify universal screening for diabetes with tests. Practitioners should be vigilant with family history of screening of diabetes. In families two or more generations of diabetes, there should be a low threshold for asymptomatic screening with a serum Hb1Ac.

HYPERTROPHIC CARDIOMYOPATHY AND MYBPC3 VARIANT - A CLINICAL CASE

Abstract Introduction Hypertrophic cardiomyopathy is a primary pathology of the cardiac muscle. Sarcomeric forms of hypertrophic cardiomyopathy (HCM) often have autosomal dominant transmission. A pathogenetic or likely pathogenetic mutation affecting genes encoding sarcomeric proteins is present in 30-60% of cases. In this study, we present a case of a family affected by hypertrophic cardiomyopathy with a mutation classified as of uncertain significance in the MYBPC3 gene. Clinical Case Mr. AA, 74 years old, attended the cardiomyopathy outpatient clinic of our hospital in June 2021 due to worsening heart failure with an hypertrophic phenotype. His medical history reported an increase in the thickness of the interventricular septum (IVS) since 1985. In 2015, the patient underwent pacemaker implantation for symptomatic 2:1 atrioventricular block associated with syncope and complete left bundle branch block. Since 2016, he had paroxysmal atrial fibrillation complicated by an ischemic stroke in 2019 with subtherapeutic INR. Cardiac magnetic resonance imaging (MRI) or genetic evaluation had never been performed. During the visit, the patient reported that his sister (AG, 73 years old) had undergone tests due to diffuse negative T waves findings in a previous ECG, revealing the presence of a long myocardial bridge of the left anterior descending artery (LAD). No family history of sudden cardiac death was reported. The echocardiogram of AA showed LV hypertrophy (septal wall thickness/posterior wall thickness 18/15 mm, respectively) with an ejection fraction of 36%. Suspecting sarcomeric HCM, a genetic test (TruSight One Expanded Illumina) was performed, revealing two variants of uncertain significance in heterozygosity in the CACNA1C - Calcium Voltage-Gated Channel Subunit Alpha1 C gene (c.2460G>C p.(Lys820Asn)) and MYBPC3 gene (c.2030C>T p.(Pro677Leu)). After a few months, AG presented MRI results suggestive of HCM apical variant (Figure 1). The genetic consultant recommended family screening, and the pedigree is shown in Figure 2. All carriers of the CACNA1C mutation had a negative phenotype. AG's son, IF, 56 years old, carriers of MYBPC3 mutation, presented an MRI compatible with early-stage HCM (Figure 3). His son, carriers of MYBPC3 mutation as well, is now awaiting a cardiac MRI. Conclusions In the family presented here, the MYBPC3 variant (c.2030C>T p.(Pro677Leu)) appears to be correlated with the development of sarcomeric hypertrophic cardiomyopathy. Registry studies with a large sample size are desirable to accurately classify variants of uncertain significance, which are becoming more common due to the widespread use of genetic tests.

Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway.

Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown. We present a case report encompassing clinical assessments, imaging studies, and whole-exome sequencing analysis, complemented by functional invitro experiments. This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation. Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.

Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A

BackgroundPseudohypoparathyroidism (PHP) is caused by loss-of-function mutations at the GNAS gene (as in the PHP type 1A; PHP1A), de novo or inherited at heterozygous state, or by epigenetic alterations at the GNAS locus (as in the PHP1B). The condition of PHP refers to a heterogeneous group of disorders that share common clinical and biological features of PTH resistance. Manifestations related to resistance to other hormones are also reported in many patients with PHP, in association with the phenotypic picture of Albright hereditary osteodystrophy characterized by short stature, round facies, subcutaneous ossifications, brachydactyly, mental retardation and, in some subtypes, obesity. The purpose of our study is to report a new mutation in the GNAS gene and to describe the significant phenotypic variability of three sisters with PHP1A bearing the same mutation.Case presentationWe describe the cases of three sisters with PHP1A bearing the same mutation but characterized by a significantly different phenotypic picture at onset and during follow-up in terms of clinical features, auxological pattern and biochemical changes. Clinical exome sequencing revealed a never before described heterozygote mutation in the GNAS gene (NM_000516.5 c.118_139 + 51del) of autosomal dominant maternal transmission in the three siblings, confirming the diagnosis of PHP1A.ConclusionsThis study reported on a novel mutation of GNAS gene and highlighted the clinical heterogeneity of PHP1A characterized by wide genotype–phenotype variability. The appropriate diagnosis has crucial implications for patient care and long-term multidisciplinary follow-up.

Clinical case of patient with Cryopyrin-associated Periodic Syndrome (Muckle-Wells syndrome) and systemic lupus erhythematodes

Muckle-Wells syndrome is a cryopyrin-associated periodic syndrome with an autosomal dominant transmission pattern. The disease characterized by episodes of step move. We present a clinical case a woman of 34-years old with cryopyrin-associated periodic syndrome (Muckle-Wells syndrome) and systemic lupus erhythematodes (SLE). Patient is a heterozygous carrier of a 3-nucleotide duplication in exon 3 of the NLRP3 gene (c.1315_1317dupGCG), inserting an alanine between amino acid positions 439 and 440 (p.Ala439dup). This mutation is a characteristic with Muckle-wells syndrome. From the clinical examination she has clinical symptoms of SLE with moderate activity from SLEDAI = 9 points (“malar rash”, arthritis, leucopenia with lymphopenia, elevated levels of ANA-antibodys and anti-dsDNA-antibodys). Patient was treatment with methylprednisolone 12 mg daily, methotrexate 15 mg weekly, colchicin 2 time of 0,5 mg daily. Over 3 months patient has partial improvement of symptoms without full reduction. On the moment patient lives in Germany and has treatment with Anakinra with excellent results and good quality of life. In the literature is not found other with connection between cryopyrin-associated periodic syndrome (Muckle-Wells syndrome) and connective tissue disease.

A rare case of Klippel–Trenaunay syndrome in a neonate

Klippel–Trenaunay syndrome (KTS) is a rare syndrome of congenital capillary-venous vascular malformation associated with altered limb bulk and/or length. It is characterised by capillary nevus, varicosities and hypertrophy of bones and tissues of the affected limb. These three features constitute the primary diagnostic criteria of this syndrome. Although the cause of this disorder is unknown, it has a sporadic occurrence with some reports mentioning autosomal dominant transmission as well. The diagnosis of this embryological malformation is mainly clinical along with supportive evidence from other imaging modalities. In this article, we report a 5-dayold male baby who had phenotypic features suggestive of KTS and was later confirmed by magnetic resonance imaging.

Differential diagnosis of chorea (guidelines of the German Neurological Society)

IntroductionChoreiform movement disorders are characterized by involuntary, rapid, irregular, and unpredictable movements of the limbs, face, neck, and trunk. These movements often initially go unnoticed by the affected individuals and may blend together with seemingly intended, random motions. Choreiform movements can occur both at rest and during voluntary movements. They typically increase in intensity with stress and physical activity and essentially cease during deep sleep stages. In particularly in advanced stages of Huntington disease (HD), choreiform hyperkinesia occurs alongside with dystonic postures of the limbs or trunk before they typically decrease in intensity.Summary or definition of the topicThe differential diagnosis of HD can be complex. Here, the authors aim to provide guidance for the diagnostic process. This guidance was prepared for the German Neurological Society (DGN) for German-speaking countries.RecommendationsHereditary (inherited) and non-hereditary (non-inherited) forms of chorea can be distinguished. Therefore, the family history is crucial. However, even in conditions with autosomal-dominant transmission such as HD, unremarkable family histories do not necessarily rule out a hereditary form (e.g., in cases of early deceased or unknown parents, uncertainties in familial relationships, as well as in offspring of parents with CAG repeats in the expandable range (27–35 CAG repeats) which may display expansions into the pathogenic range).ConclusionsThe differential diagnosis of chorea can be challenging. This guidance prepared for the German Neurological Society (DGN) reflects the state of the art as of 2023.

Characterization and natural history of phenotypes in hereditary transthyretin amyloidosis

Abstract Background Hereditary systemic amyloidosis (ATTRv), caused by mutations in the transthyretin (TTR) gene, is a rare systemic disease with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Purpose The purpose of this study was to describe the population of individuals with pathogenic mutations for TTR, comparing the genotype and clinical-instrumental characteristics of patients based on phenotype. Subsequently, the disease course was investigated in terms of the onset of new clinical manifestations, survival, and hospitalizations for heart failure. Methods Clinical and instrumental data from 325 consecutive patients carrying a pathogenic mutation of the TTR gene (asymptomatic carriers, n=106; cardiac phenotype, n=49; neurological phenotype, n=49; mixed phenotype, n=121) were analyzed at Our Center between 1979 and August 2022. Results A total of 23 different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most represented. Dominant mutations were found in patients with cardiac and neurological phenotypes, respectively Ile68Leu and Val30Met, while patients with mixed phenotype had marked genotypic variability. Patients with cardiac amyloidosis (CA) were predominantly male and had a more advanced NYHA functional class at presentation, while subjects with neurological involvement showed greater motor disabilities. There was also a significant difference in the age of disease diagnosis between the three groups: cardiac phenotype 73.2 years (IQR 66.5 – 78.1), mixed phenotype 58.4 years (IQR 47- 66.3), neurological phenotype 44 years (IQR 33.5 – 62.9). At the end of a median follow-up of 51 months (IQR 24 – 90 months), data from 290 subjects were analyzed, of whom 111 (38.3%) died and 123 (42.4%) had a major clinical event, including death or hospitalization for heart failure. Subjects without signs of disease had a prognosis similar to that of the healthy population, while patients with CA, with or without neurological manifestations, had a worse overall and event-free survival compared to those with isolated neurological phenotype. On multivariate analysis, age at diagnosis, NYHA functional class, and an mPND score ³ 2 were independently associated with adverse clinical events. Conclusions This study confirms the important clinical heterogeneity of patients with ATTRv, where three main phenotypes can be identified, characterized by specific clinical, demographic, and instrumental features. Although in some cases it is possible to identify a genotype-phenotype correlation, the extreme variability of clinical presentation is evident even among patients sharing the same mutation. In the study cohort, patients with CA had a worse prognosis. However, this finding should be interpreted with caution because it is influenced by disease-modifying therapy, which was performed unevenly among the three phenotypes.Univariate and multivariateKaplan-Meier curves

Titin copy number variations associated with dominant inherited phenotypes

BackgroundTitinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very...

Alzheimer's disease as a viral disease: Revisiting the infectious hypothesis.

Alzheimer's disease (AD) represents the most frequent type of dementia in elderly people. Two major forms of the disease exist: sporadic - the causes of which have not yet been fully understood - and familial - inherited within families from generation to generation, with a clear autosomal dominant transmission of mutations in Presenilin 1 (PSEN1), 2 (PSEN2) or Amyloid Precursors Protein (APP) genes. The main hallmark of AD consists of extracellular deposits of amyloid-beta (Aβ) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein. An ever-growing body of research supports the viral infectious hypothesis of sporadic forms of AD. In particular, it has been shown that several herpes viruses (i.e., HHV-1, HHV-2, HHV-3 or varicella zoster virus, HHV-4 or Epstein Barr virus, HHV-5 or cytomegalovirus, HHV-6A and B, HHV-7), flaviviruses (i.e., Zika virus, Dengue fever virus, Japanese encephalitis virus) as well as Human Immunodeficiency Virus (HIV), hepatitis viruses (HAV, HBV, HCV, HDV, HEV), SARS-CoV2, Ljungan virus (LV), Influenza A virus and Borna disease virus, could increase the risk of AD. Here, we summarized and discussed these results. Based on these findings, significant issues for future studies are also put forward.

Mutation in CHEK2 and hereditary breast cancer: A case report

Breast Cancer (BC) is the cancer that ranks first in incidence and mortality among women. It is estimated that 5 to 10% of BC cases develop in patients who carry a hereditary predisposition associated with autosomal dominant transmission and high penetrance susceptibility genes.

The genetic aspects of hidradenitis suppurativa

Genetic aspects have a substantial role in hidradenitis suppurativa (HS) pathogenesis. A positive family history of HS occurs in about one-third of HS cases and is significantly higher in patients with early onset of the disease. Recent twin studies have shown a high heritability in HS, fortifying the importance of genetic factors in disease pathogenesis. Based on existing knowledge on the genomics of HS, the disease can be categorized as familial HS, sporadic, syndromic HS, and “HS plus” associated with other syndromes. In familial HS, autosomal dominant transmission is proposed, and monogenic inheritance is rare. This monogenic trait is related to mutations of γ-secretase component genes and Notch signaling or defects in inflammasome function. With newly discovered gene mutations, such as those related to innate and adaptive immunity, skin microbiome, inflammasome, epidermal homeostasis, and keratinization pathway, we can define HS as a polygenic, multifactorial, autoinflammatory disease. To fully elucidate the genetic aspects of HS, we need extensive, long-term global collaborations.

Split Hand-Foot and Deafness in a Patient with 7q21.13-q21.3 Deletion Not Including the DLX5/6 Genes.

Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays. It may occur as part of a syndromic condition or as an isolated malformation. The most common of the six genetic loci identified for this condition is correlated to SHFM1 and maps in the 7q21q22 region. SHFM1 is characterized by autosomal dominant transmission, incomplete penetrance and variable expressivity. Associated features often include hearing loss, intellectual disability/developmental delay and craniofacial abnormalities. Disruption of the DLX5/DLX6 genes, mapping within the SHFM1 locus, is now known to be responsible for the phenotype. Through SNP array, we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I); we identified a deletion in 7q21, not involving the DLX5/6 genes, but including exons 15 and 17 of DYNC1I1, known to act as exonic enhancers (eExons) of the DLX5/6 genes. We further demonstrated the role of DYNC1I1 eExons in regulating DLX5/6 expression by means of showing a reduced expression of the DLX5/6 genes through RT-PCR in a patient-derived lymphoblastoid cell line. Furthermore, our data and a review of published cases do not support the hypothesis that DLX5/6 are imprinted in humans. This work is an example of how the disruption of regulatory elements can be responsible for congenital malformations.

Identification by Exome Sequencing of Predisposing Variants in Familial Cases of Autoinflammatory Recurrent Fevers.

Periodic fever syndromes include autoinflammatory disorders (AID) that involve innate immunity. These disorders are characterized by recurrent fevers and aberrant multi-organ inflammation, without any involvement of T or B cells or the presence of autoantibodies. A complex genetic architecture has been recognized for many AID. However, this complexity has only been partially uncovered for familial Mediterranean fever and other conditions that have a classical monogenic origin and Mendelian transmission. Several gene panels are currently available for molecular diagnosis in patients suspected of having AID. However, even when an extensive number of genes (up to 50-100) are tested in a cohort of clinically selected patients, the diagnostic yield of AID ranges between 15% and 25%, depending on the clinical criteria used for patient selection. In the remaining 75-85% of cases, it is conceivable that the causative gene or genes responsible for a specific condition are still elusive. In these cases, the disease could be explained by variants, either recessive or dominant, that have a major effect on unknown genes, or by the cumulative impact of different variants in more than one gene, each with minor additive effects. In this study, we focused our attention on five familial cases of AID presenting with classical autosomal dominant transmission. To identify the probable monogenic cause, we performed exome sequencing. Through prioritization, filtering, and segregation analysis, we identified a few variants for each family. Subsequent bioinformatics evaluation and pathway analysis helped to narrow down the best candidate genes for each family to FCRL6, PKN1, STAB1, PTDGR, and VCAM1. Future studies on larger cohorts of familial cases will help confirm the pathogenic role of these genes in the pathogenesis of these complex disorders.

#6286 NEPHROCALCINOSIS IN 3 GENERATIONS OF FEMALE PATIENTS DUE TO A PATHOGENIC MEN1 MUTATION

Abstract Background and Aims Multiple Endocrince Neoplasia type 1 (MEN1) syndrome, has an autosomal dominant transmission pattern, characterized by hyperparathyroidism, benign or malignant tumors in pancreas islets, pituitary tumors, thymic carcinomas, adrenal cortex adenomas and angio-fibromas of the skin. We are describing 2 cases of MEN1 with first and cardinal manifestations within the kidney. Method Medical records review, whole exome sequencing (WES), bioinformatics analysis by Ingenuity Pathway Analysis, QIAGEN Results Patient 1. A 28 year old female presented with horseshoe kidney, multiple pyelonephritis episodes, primary hyperparathyroidism, hypercalcemia, magnesiuria, reduced bone mass, and nephrocalcinosis. Her mother and grandmother suffered from hyperparathyroidism. WES analysis demonstrated a 12-base deletion between intron 9 and exon 10 in MEN1 gene (c.1351-3_1359delCAGGTGCGGCAG) with an apparent pathogenicity [1]. An accompanying alteration of CLDN16 gene (c.324+13C>G, rs369250510) was also detected. Till now this alteration is considered benign. Patient 2. A 48 year old female, with primary hyperparathyroidism in the last 15 years (the mother of Patient 1), with nephrocalcinosis since 1997 (calcium oxalate stones), preserved renal function, hypercalcemia, magnesiuria, reduced bone mass, hypertelorism with concurrent diplopia. In 2013, parathyroeidectomy resulted in stabilization of nephrocalcinosis. WES revealed the same pathogenic deletion as in her daughter. A research for epigastric pain revealed a cystic pancreatic mass, with accompanying increase in serum gastrin and chromogranin. A pituitary adenoma is manifested with a marginally increased serum prolactin. Her mother suffers from primary hyperparathyroidism with nephrocalcinosis. Conclusion In familial nephrocalcinosis/lithiasis/hyperparathyroidism genetic counselling and screening defines individualized treatment and may prevent extra renal disease manifestations.

Subcapsular Hematoma of The Liver Revealing RENDU-OSLER Disease: About A Pediatric Case

RENDU-OSLER's disease is a rare hereditary disease of autosomal dominant transmission, it is a condition characterized by mucocutaneous and visceral telangiectasias; often revealed by recurrent epistaxis, hemostasis can be difficult. We report the observation of a 10-year-old girl who presented with chronic abdominal pain secondary to a subcapsular hematoma of the liver due to the rupture of an arteriovenous malformation falling within the framework of RENDU- OSLER

Touraine-Solente-Gole syndrome: pathogenic variant in SLCO2A1 presented with polyarthralgia and digital clubbing

BackgroundPrimary Hypertrophic Osteoarthropathy (PHO), also known as Touraine-Solente-Gole Syndrome, is a rare, multisystemic autosomal recessive disorder caused by pathogenic variants in the 15-hydroxyprostaglandin dehydrogenase (HPGD) or Solute Carrier Organic Anion Transporter Family Member 2A1 (SLCO2A1) genes. However, autosomal dominant transmission has also been described in some families with incomplete penetrance. PHO usually starts in childhood or adolescence, presenting with digital clubbing, osteoarthropathy, and pachydermia. We described a complete form of the syndrome in a male patient with a homozygous variant in the SLCO2A1 gene (c.1259G > T).Case presentationA 20-year-old male was referred to our Pediatric Rheumatology Clinic with a five-year history of painful and swollen hands, knees, ankles and feet, prolonged morning stiffness and relief with non-steroidal antiinflammatory drugs. He also reported late onset facial acne and palmoplantar hyperhidrosis. Family history was irrelevant and parents were non-consanguineous. On clinical examination, he presented clubbing of the fingers and toes, moderate acne and marked facial skin thickening with prominent scalp folds. He had hand, knee, ankles and feet swelling. Laboratory investigations showed elevated inflammatory markers. Complete blood count, renal and hepatic function, bone biochemistry were normal, as well as immunological panel. Plain radiographs revealed soft tissue swelling, periosteal ossification and cortical thickening of the skull, phalanges, femur and toe acroosteolysis. Due to the absence of other clinical signs suggesting a secondary cause, we suspected PHO. A genetic study revealed a likely pathogenic variant, c.1259G > T(p.Cys420Phe), in homozygosity in the SLCO2A1 gene, thus confirming the diagnosis. The patient started oral naproxen with significant clinical improvement.ConclusionsPHO should be kept in the differential diagnosis of inflammatory arthritis affecting children, often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). To the best of our knowledge, this is the second genetically confirmed case of PHO in a Portuguese patient (first variant c.644 C > T), both made at our department.