[Diagnosis of a rare and severe inflammatory bowel disease in an infant with peri-orificial ulcerations]. / Diagnostic d'une maladie inflammatoire rare et sévère de l'intestin chez un nourrisson présentant des ulcérations péri-orificielles.

We report the case of an infant aged 8 and a half months, who had an apparent life-threatening event and died despite optimal resuscitation management. The medical history was marked by mild symptoms, mainly feeding difficulties and progressively settling skin lesions. Parents were related (first cousins) and the patient had two healthy older sisters. Autopsy showed growth delay, symmetrical erythematous and ulcerated periorificial lesions associated with punctiform erythematous lesions of the face and alopecia. Microscopic examination revealed deep bronchial inhalation with the onset of infectious pneumopathy, major inflammatory ulceration of the gastrointestinal tract, hepatic steatosis, brain stem and pancreas abnormalities. We conclude that the cause of death was a multi-visceral failure with inhalation pneumopathy, in a context of very early onset inflammatory bowel disease (VEO-IBD). Genetic consultation, into a rare disease reference center, allowed to orient the analysis, to identify a homozygous pathogenic variant in the IL10RA gene, confirming the diagnostic of an autosomal recessive very early onset inflammatory bowel disease (inflammatory bowel disease 28, early-onset, autosomal recessive, #613148).

Genetic Enteropathies Linked to Epithelial Structural Abnormalities and Enteroendocrine Deficiency: A Systematic Review.

OBJECTIVES: Congenital diarrhea and enteropathies linked to epithelial structural abnormalities constitute 3 different rare diseases: the tufting enteropathies (TE; EPCAM and SPINT2 mutations), microvillous inclusion disease (MVID; MYO5B and STX3 mutations), and tricho-hepato-enteric syndrome (THE; TTC37 and SKIV2L mutations). Moreover, enteroendocrine deficiencies (ED; PCSK1 and NEUROG3 mutations) share common clinical characteristics with TE, THE, and MVID in that the treatment requires, in most cases, long-term parenteral nutrition. Although numerous cases have been reported in the literature, aggregated data on morbidity and mortality are missing owing to the rarity of the diseases. METHODS: We performed a systematic review of all published cases and retrieved 86 articles describing 323 patients (164 boys and 135 girls). RESULTS: The mortality rate was 20.28%, with a median age at death of 13.5 months (range 0-228 months); the mortality risk was 30.8/1000 person-year; in half of the cases, death was caused by infections. Parenteral nutrition was required in 95.4% of patients and weaning off from parenteral nutrition was achieved in 29.35% at a median age of 23 months (range 3.3-276 months). The patients with ED linked to PCSK1 were nearly all weaned at a median age of 14 months, but most of the patients became overweight. MVID patients with MYO5B mutations were most often born preterm. ED linked to NEUROG3 mutation and THE patients usually presented with intrauterine growth retardation. CONCLUSIONS: This review presents data from 323 patients with congenital diarrhea linked to EPCAM TE, SPINT2 TE, TTC37 THE, SKIV2L THE, MYO5B MVID, STX3 MVID, NEUROG3 ED, and PCSK1 ED mutations.

Prenatal biochemical diagnosis of two forms of congenital diarrheal disorders (congenital chloride diarrhea and congenital sodium diarrhea): A series of 12 cases.

OBJECTIVE: Congenital diarrheal disorders (CDDs) are a group of rare diseases among which some present as inherited disorders of intestinal electrolyte transportation: congenital chloride diarrhea (CCD) and congenital sodium diarrhea (CSD) with prenatal manifestations, mainly polyhydramnios, leading to premature delivery. Affected neonates present with watery stools, sometimes mistaken as urine, leading to a misdiagnosis of Bartter syndrome. The aim of this study was to study the value of a prenatal biochemical pattern in the case of suspected CDD. METHODS: We retrospectively studied 12 amniotic fluids of CDD-affected fetuses prenatally suspected and confirmed after birth. Digestive enzymes, proteins, and electrolytes were assayed and showed abnormal biochemical patterns. RESULTS: The 12 infants (eight CCD- and four CSD-affected) were born prematurely with a normal birth weight. Electrolytes and the Bartter index were normal for all cases. Amniotic fluid enzyme patterns were abnormal: anal leakage for nine, as expected, but vomiting of bile was observed for three infants, for whom an occlusive syndrome required surgery, and thereafter severe complications appeared with a poor prognosis. CONCLUSION: Amniotic fluid biochemical patterns differentiate CDD from Bartter syndrome. If a vomiting bile pattern is observed, postnatal management should take into account the hypothesis of a most severe complication.

Portal vein stenosis preconditioning of living donor liver in swine: early mechanisms of liver regeneration and gain of hepatic functional mass.

To reduce the morbidity and mortality risk for the donor in living donor liver transplantation (LDLT), we previously identified 20% left portal vein (LPV) stenosis as an effective preconditioning method to induce cell proliferation in the contralateral lobe without downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours after preconditioning and investigate the changes in liver volume and function. Fourteen pigs were used this study. Five pigs were used to study the genetic, cellular and molecular mechanisms set up in the early hours following the establishment of our preconditioning. The remaining nine pigs were equally divided into three groups: sham-operated animals, 20% LPV stenosis, and 100% LPV stenosis. Volumetric scanning and 99 mTc-Mebrofenin hepatobiliary scintigraphy were performed before preconditioning and 14 days after to study morphological and functional changes in the liver. We demonstrated that liver regeneration triggered by 20% LPV stenosis in the contralateral lobe involves TNF-α, IL-6, and inducible nitric oxide synthase 2 by means of STAT3 and hepatocyte growth factor. We confirmed that our preconditioning was responsible for an increase in the total liver volume. Finally, we demonstrated that this volumetric gain was associated with an increase in hepatic functional capacity. NEW & NOTEWORTHY We describe a new preconditioning method for major hepatectomy that is applicable to hepatectomy for donation. We identified 20% left portal vein stenosis as effective preconditioning that is capable of inducing cell proliferation in the contralateral lobe without the downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours following preconditioning, and we confirm that 20% left portal vein stenosis is responsible for an increase in the functional capacity and total liver volume in a porcine model.

Arginase upregulation and eNOS uncoupling contribute to impaired endothelium-dependent vasodilation in a rat model of intrauterine growth restriction.

Individuals born after intrauterine growth restriction (IUGR) are at increased risk of developing cardiovascular diseases in adulthood, notably hypertension (HTN). Alterations in the vascular system, particularly impaired endothelium-dependent vasodilation, may play an important role in long-term effects of IUGR. Whether such vascular dysfunction precedes HTN has not been fully established in individuals born after IUGR. Moreover, the intimate mechanisms of altered endothelium-dependent vasodilation remain incompletely elucidated. We therefore investigated, using a rat model of IUGR, whether impaired endothelium-dependent relaxation precedes the development of HTN and whether key components of the l-arginine-nitric oxide (NO) pathway are involved in its pathogenesis. Pregnant rats were fed with a control (CTRL, 23% casein) or low-protein diet (LPD, 9% casein) to induce IUGR. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography in 5- and 8-wk-old male offspring. Aortic rings were isolated to investigate relaxation to acetylcholine, NO production, endothelial NO synthase (eNOS) protein content, arginase activity, and superoxide anion production. SBP was not different at 5 wk but significantly increased in 8-wk-old offspring of maternal LPD (LP) versus CTRL offspring. In 5-wk-old LP versus CTRL males, endothelium-dependent vasorelaxation was significantly impaired but restored by preincubation with l-arginine or the arginase inhibitor S-(2-boronoethyl)-l-cysteine; NO production was significantly reduced but restored by l-arginine pretreatment; total eNOS protein, dimer-to-monomer ratio, and arginase activity were significantly increased; superoxide anion production was significantly enhanced but normalized by pretreatment with the NO synthase inhibitor Nω-nitro-l-arginine. In this model, IUGR leads to early-impaired endothelium-dependent vasorelaxation, resulting from arginase upregulation and eNOS uncoupling, which precedes the development of HTN.

The magnitude of nephron number reduction mediates intrauterine growth-restriction-induced long term chronic renal disease in the rat. A comparative study in two experimental models.

BACKGROUND: Intrauterine growth restriction (IUGR) is a risk factor for hypertension (HT) and chronic renal disease (CRD). A reduction in the nephron number is proposed to be the underlying mechanism; however, the mechanism is debated. The aim of this study was to demonstrate that IUGR-induced HT and CRD are linked to the magnitude of nephron number reduction, independently on its cause. METHODS: Systolic blood pressure (SBP), glomerular filtration rate (GFR), proteinuria, nephron number, and glomerular sclerosis were compared between IUGR offspring prenatally exposed to a maternal low-protein diet (9% casein; LPD offspring) or maternal administration of betamethasone (from E17 to E19; BET offspring) and offspring with a normal birth weight (NBW offspring). RESULTS: Both prenatal interventions led to IUGR and a similar reduction in birth weight. In comparison to NBW offspring, BET offspring had a severe nephron deficit (-50% in males and -40% in females, p < 0.01), an impaired GFR (-33%, p < 0.05), and HT (SBP+ 17 mmHg, p < 0.05). Glomerular sclerosis was more than twofold higher in BET offspring than in NBW offspring (p < 0.05). Long-term SBP, GFR, and glomerular sclerosis were unchanged in LPD offspring while the nephron number was moderately reduced only in males (-28% vs. NBW offspring, p < 0.05). CONCLUSION: In this study, the magnitude of nephron number reduction influences long term renal disease in IUGR offspring: a moderate nephron number is an insufficient factor. Extremely long-term follow-up of adults prenatally exposed to glucocorticoids are required.

High protein intake in neonatal period induces glomerular hypertrophy and sclerosis in adulthood in rats born with IUGR.

BACKGROUND: Intrauterine growth restriction (IUGR) and postnatal nutrition are risk factors for cardiovascular and renal diseases in both humans and animals. The long-term renal effects of protein intake early in life remain unknown. The objective was to evaluate the effects of a neonatal feeding with high protein (HP) milk on renal functions and structure in IUGR male rats. METHODS: Maternal gestational low protein diet was used to produce IUGR. At day 5, IUGR pups were gastrostomized in the "pup-in-the cup" model and received either normal protein (NP) milk or HP (+50% protein content) milk until day 21. After weaning, the animals were fed the same standard diet. Renal functions and structure were assessed at postnatal day 18 (D18) and in adult offspring. RESULTS: During the preweaning period, the postnatal weight gain between the two groups was unaffected. On D18, kidneys from HP offspring were heavier with significant glomerular hypertrophy (+40%, P < 0.05). HP diet was associated with significant proteinuria and glomerulosclerosis (+49%, P < 0.05). Glomerular number was unaltered. CONCLUSION: Neonatal HP feeding following IUGR affects renal functions and structure at adulthood. These alterations may result from a single nephron glomerular hyperfiltration.

Transcriptomic analysis of human placenta in intrauterine growth restriction.

BACKGROUND: Intrauterine growth restriction (IUGR) is a frequent complication of pregnancy defined as a restriction of fetal growth. The objective of this work was to improve the knowledge on the pathophysiology of IUGR using a genome-wide method of expression analysis. METHODS: We analyzed differentially expressed genes in pooled placental tissues from vascular IUGR (four pools of three placentas) and normal pregnancies (four pools of three placentas) using a long nucleotide microarray platform (Nimblegen). We first did a global bioinformatics analysis based only on P value without any a priori. We secondly focused on "target" genes among the most modified ones. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed on an extended panel of tissue samples (n = 62) on selected "target". RESULTS: We identified 636 modified genes among which 206 were upregulated (1.5 and higher; P < 0.05). Groups of patients were classified unambiguously. Genes involved in mitochondrial function and oxidative phosphorylation were decreased affecting three out of five complexes of the respiratory chain of the mitochondria, and thus energy production and metabolism. Among the most induced genes, we identified LEP, IGFBP1, and RBP4. CONCLUSION: Complementary studies on the role and function of LEP, IGFBP1, and RBP4 in IUGR pathophysiology and also in fetal programming remain necessary.

Placental macrophages are impaired in chorioamnionitis, an infectious pathology of the placenta.

Pregnancy is dependent on maternal-fetal tolerance that may be compromised because of infections or inflammation of the placenta. In this study, we examined whether the context of placental immune tolerance affected the functions of resident macrophages and if their functions were altered during chorioamnionitis, an infectious pathology of the placenta. Macrophages from at-term placentas expressed CD14, exhibited macrophage microbicidal functions, but were less inflammatory than monocyte-derived macrophages. Moreover, placental macrophages spontaneously matured into multinucleated giant cells (MGCs), a property not exhibited by monocyte-derived macrophages, and we detected MGCs of myeloid origin in placental tissue. Compared with placental macrophages, MGCs exhibited a specific phenotype and gene expression signature, consisting of increased cytoskeleton-associated gene expression along with depressed expression of inflammatory response genes. Furthermore, placental macrophages from patients with chorioamnionitis were unable to form MGCs, but this defect was partially corrected by incubating these placental macrophages with control trophoblast supernatants. MGCs formation likely serves to regulate their inflammatory and cytocidal activities in a context that imposes semiallograft acceptance and defense against pathogens.

Preeclamptic plasma induces transcription modifications involving the AP-1 transcriptional regulator JDP2 in endothelial cells.

Preeclampsia is a pregnancy disorder characterized by hypertension and proteinuria. In preeclampsia, the placenta releases factors into the maternal circulation that cause a systemic endothelial dysfunction. Herein, we investigated the effects of plasma from women with preeclamptic and normal pregnancies on the transcriptome of an immortalized human umbilical vein endothelial cell line. The cells were exposed for 24 hours to preeclamptic or normal pregnancy plasma and their transcriptome was analyzed using Agilent microarrays. A total of 116 genes were found differentially expressed: 71 were up-regulated and 45 were down-regulated. In silico analysis revealed significant consistency and identified four functional categories of genes: mitosis and cell cycle progression, anti-apoptotic, fatty acid biosynthesis, and endoplasmic reticulum stress effectors. Moreover, several genes involved in vasoregulation and endothelial homeostasis showed modified expression, including EDN1, APLN, NOX4, and CBS. Promoter analysis detected, among the up-regulated genes, a significant overrepresentation of genes containing activation protein-1 regulatory sites. This correlated with down-regulation of JDP2, a gene encoding a repressor of activation protein-1. The role of JDP2 in the regulation of a subset of genes in the human umbilical vein endothelial cells was confirmed by siRNA inhibition. We characterized transcriptional changes induced by preeclamptic plasma on human umbilical vein endothelial cells, and identified, for the first time to our knowledge, JDP2 as a regulator of a subset of genes modified by preeclamptic plasma.

Undercorrection of hypernatremia is frequent and associated with mortality.

BACKGROUND: About 1% of patients admitted to the Emergency Department (ED) have hypernatremia, a condition associated with a mortality rate of 20 to 60%. Management recommendations originate from intensive care unit studies, in which patients and medical diseases differ from those in ED. METHODS: We retrospectively studied clinical characteristics, treatments, and outcomes of severely hypernatremic patients in the ED and risk factors associated with death occurrence during hospitalization. RESULTS: During 2010, 85 cases of severe hypernatremia ≥ 150 mmol/l were admitted to ED. Hypernatremia occurred in frail patients: mean age 79.7 years, 55% institutionalized, 28% with dementia.Twenty four percent of patients died during hospitalization. Male gender and low mean blood pressure (MBP) were independently associated with death, as well as slow natremia correction speed, but not the severity of hyperosmolarity at admission. Infusion solute was inappropriate for 45% of patients with MBP <70 mmHg who received hypotonic solutes and 22% of patients with MBP ≥ 70 mmHg who received isotonic solutes or were not perfused. CONCLUSIONS: This is the first study assessing outcome of hypernatremic patients in the ED according to the treatment provided. It appears that not only a too quick, but also a too slow correction speed is associated with an increased risk of death regardless of initial natremia. Medical management of hypernatremic patients must be improved regarding evaluation and treatment.

Total serum tryptase levels are higher in young infants.

BACKGROUND: Mast cells participate in immune defense and allergic disease. At baseline, serum tryptase levels primarily reflect mast cell burden, while mast cell degranulation leads to granule tryptase release, which may be detectable as a transitory elevation of serum tryptase levels. Thus, mast cell burden and mast cell activity are reflected by serum tryptase levels, but reports are scarce in infants under 1 yr. We aimed at defining levels of total serum tryptase levels in this population. METHODS: Total serum tryptase levels (ImmunoCAP; Phadia) were measured in 372 sera from infants younger than 1 yr. Two hundred and forty-two sera came from non-atopic, non-allergic infants in good condition, who had blood drawn for routine follow-up or diagnosis of illnesses that are not known to induce changes in serum tryptase levels. Seventy-two sera were from atopic and/or allergic infants, and 58 sera were from non-atopic, non-allergic infants requiring intensive care. RESULTS: Median serum tryptase levels were highest in infant2s under 3 months (6.12 ± 3.47 µg/l) and gradually decreased before reaching levels similar to those described in adults and older children (3.85 ± 1.8 µg/l between 9 and 12 months). Atopic/allergic status was associated with even higher tryptase levels (14.20 ± 10.22 µg/l in infants younger than 3 months). Intensive care patients had lower levels of serum tryptase (4.12 ± 3.38 µg/l in infants younger than 3 months). Longitudinal follow-up was performed in 27 patients and showed tryptase levels decrease over time in individual patients. Infants'sex was not found to interfere with serum tryptase levels. CONCLUSION: Total serum tryptase levels are significantly higher in younger infants compared with older ones. In infants of the same age, serum tryptase levels may vary according to the clinical condition and thus suggest mast cell involvement in the physiologic as well as in the allergic immune responses of young infants.

Adverse consequences of accelerated neonatal growth: cardiovascular and renal issues.

Epidemiological and experimental studies show that the risk of cardiovascular and metabolic diseases at adulthood is inversely related to the weight at birth. Although with less evidence, low birth weight has been suggested to increase the risk of chronic kidney disease (CKD). It is well established that the developmental programming of arterial hypertension and of renal disease involves in particular renal factors, especially nephron endowment, which is reduced in low birth weight and maternal diabetes situations. Experimental studies, especially in rodents, have demonstrated the long-term influence of postnatal nutrition and/or postnatal growth on cardiovascular, metabolic and renal functions, while human data are scarce on this issue. Vascular and renal diseases appear to have a "multihits" origin, with reduced nephron number the initial hit and rapid postnatal growth the second hit. This review addresses the current understanding of the role of the kidney, both as a mechanism and as a target, in the developmental origins of adult disease theory, with a particular focus on the long-term effects of postnatal growth and nutrition.

Low Vitamin D Levels at Birth and Early Respiratory Outcome in Infants With Gestational Age Less Than 29 Weeks.

BACKGROUND: Vitamin D (VitD) is involved in lung development but its influence on respiratory distress syndrome of extremely preterm (EPT) infants have been little investigated. In this study, we examined the influence of low vitamin D status at birth on early respiratory outcomes of this vulnerable infant population. METHODS: Cord blood 25(OH)D levels ≤ 75 nmol/L were considered as Low vitamin D levels. Stepwise logistic regression and classification regression-tree analyses were used and the primary outcome was the combined outcome of death or mechanical ventilation need by the end of the first week (death or MV DoL7) as a marker od RDS severity. RESULTS: The mean (SD) GA and birth weight were 26 (1.4) weeks and 801 (212) gr, respectively; 81/109 (74%) infants had low 25(OH)D levels. Infants with low VitD levels had 25% higher initial FiO2 levels (p < 0.05) and were more likely to be mechanically ventilated on DoL7 (36 vs. 7%, p < 0.05). Adjusted for gestational age, they had 10-fold higher odds of death or MV DoL7 (p < 0.01). By regression tree analysis, the rate of death or MV DoL7 increased from 18 to 71% in infants with GA < 26 weeks and with cord blood 25(OH)D levels higher and lower than 74 nmol/L, respectively (p < 0.05). CONCLUSION: Low vitamin D levels at birth are associated with early adverse respiratory outcomes in infants with GA less 29 weeks. Further largest studies are needed to confirm this association.

An AI-Powered Blood Test to Detect Cancer Using NanoDSF.

Glioblastoma is the most frequent and aggressive primary brain tumor. Its diagnosis is based on resection or biopsy that could be especially difficult and dangerous in the case of deep location or patient comorbidities. Monitoring disease evolution and progression also requires repeated biopsies that are often not feasible. Therefore, there is an urgent need to develop biomarkers to diagnose and follow glioblastoma evolution in a minimally invasive way. In the present study, we described a novel cancer detection method based on plasma denaturation profiles obtained by a non-conventional use of differential scanning fluorimetry. Using blood samples from 84 glioma patients and 63 healthy controls, we showed that their denaturation profiles can be automatically distinguished with the help of machine learning algorithms with 92% accuracy. Proposed high throughput workflow can be applied to any type of cancer and could become a powerful pan-cancer diagnostic and monitoring tool requiring only a simple blood test.

Leptin and insulin in young adulthood are associated with weight in infancy.

Low weight in early infancy is a known risk factor for cardio-metabolic syndrome in adult life. However, little is known either about developmental programming in subjects of normal birthweight or about events between the ages which separate early programming and the occurrence of disease at late adulthood. We tested the hypothesis that circulating concentrations of leptin, adiponectin and insulin in young, healthy adults, born with a birth size within the normal range, are influenced by early life growth patterns. In an observational study of 188 healthy volunteers aged 18-25 years (97 males, 91 females) we investigated the association of metabolic function with their birth size, their growth during childhood and their body composition. High plasma leptin in early adulthood, a risk factor for cardio-metabolic syndrome, was associated with low weight at age 2 years (correlation coefficient controlled for adult weight = -0.21, P < 0.01). It was also positively associated with pre-prandial insulin and with HOMA (Homeostasis Model Assessment) insulin resistance. Leptin, leptin-adiponectin ratio and insulin correlated with lean mass, fat mass and percent fat (P < 0.0001). In conclusion, high leptin in early adulthood was associated with both low weight at age 2 years and insulin resistance. We speculate that high leptin is developmentally programmed and can contribute to the association between low weight in early infancy and increased cardio-metabolic risk in adulthood in healthy subjects.

Early postnatal overfeeding induces early chronic renal dysfunction in adult male rats.

Low birth weight is associated with an increased risk of hypertension and renal dysfunction at adulthood. Such an association has been shown to involve a reduction of nephron endowment and to be enhanced by accelerated postnatal growth in humans. However, while low-birth-weight infants often undergo catch-up growth, little is known about the long-term vascular and renal effects of accelerated postnatal growth. We surimposed early postnatal overfeeding (OF; reduction of litter size during the suckling period) to appropriate-birth-weight (NBW+OF) and intrauterine growth restriction (IUGR; IUGR+OF) pups, obtained after a maternal gestational low-protein diet. Blood pressure (systolic blood pressure; SBP) and renal function (glomerular filtration rate; GFR) were measured in young and aging offspring. Glomerulosclerosis and nephron number were determined in aging offspring (22 mo). Nephron number was reduced in both IUGR and IUGR+OF male offspring (by 24 and 26%). GFR was reduced by 40% in 12-mo-old IUGR+OF male offspring, and both NBW+OF and IUGR+OF aging male offspring had sustained hypertension (+25 mmHg) and glomerulosclerosis, while SBP and renal function were unaffected in IUGR aging offspring. Female offspring were unaffected. In conclusion, in this experimental model, early postnatal OF in the neonatal period has major long-lasting effects. Such effects are gender dependent. Reduced nephron number alone, associated with IUGR, may not be sufficient to induce long-lasting physiological alterations, and early postnatal OF acts as a "second hit." Early postnatal OF is a suitable model with which to study the long-term effects of postnatal growth in the pathogenesis of vascular disorders and renal disease.

Case Report on a Rare Disease in Lithuania: Congenital Chloride Diarrhea.

Congenital chloride diarrhea (CCD) is a rare disease, manifesting with secretory diarrhea and life-threatening electrolyte imbalance during infancy. The early diagnosis of CCD is therefore necessary for the adequate treatment. The long-term prognosis of properly managed CCD is favorable. We present a case of complicated CCD with necrotizing enterocolitis. The child was born to nonconsanguineous parents of Lithuanian origin. CCD was suspected due to watery diarrhea, progressive hypochloremia, and high fecal chlorides. Despite oral electrolytes being prescribed, volvulus of small intestine developed requiring several surgical interventions. The clinical diagnosis of CCD was confirmed by molecular genetic testing of SLC26A3 , which revealed two Polish founder mutations in the DNA of the patient. The prevalence of CCD in Lithuanian neighbor Poland is approximately 1 in 200,000 live births. This is the first described case of CCD in Lithuania to our knowledge, leading to the suggestion that this disease may be underdiagnosed.