Case Report: Liver Transplantation in Homozygous Familial Hypercholesterolemia (HoFH)-Long-Term Follow-Up of a Patient and Literature Review.

Homozygous familial hypercholesterolemia (HoFH) is a rare inherited metabolic disorder, frequently leading to an early cardiovascular death if not adequately treated. Since standard medications usually fail to reduce LDL-cholesterol (LDL-C) levels satisfactorily, LDL-apheresis is a mainstay of managing HoFH patients but, at the same time, very burdensome and suboptimally effective. Liver transplantation (LT) has been previously shown to be a promising alternative. We report on a 14 year-long follow-up after LT in a HoFH patient. At the age of 4, the patient was referred to our institution because of the gradually increasing number of xanthomas on the knees, elbows, buttocks, and later the homozygous mutation c.1754T>C (p.Ile585Thr) on the LDL-receptor gene was confirmed. Despite subsequent intensive treatment with the combination of diet, statins, bile acid sequestrant, probucol, and LDL-apheresis, the patient developed valvular aortic stenosis and aortic regurgitation by 12 years. At 16 years, the patient successfully underwent deceased-donor orthotopic LT. Nine years post-LT, we found total regression of the cutaneous xanthomas and atherosclerotic plaques and with normal endothelial function. Fourteen years post-LT, his clinical condition remained stable, but LDL-C levels have progressively risen. In addition, a systematic review of the literature and guidelines on the LT for HoFH patients was performed. Six of the 17 identified guidelines did not take LT as a treatment option in consideration at all. But still the majority of guidelines suggest LT as an exceptional therapeutic option or as the last resort option when all the other treatment options are inadequate or not tolerated. Most of the observed patients had some kind of cardiovascular disease before the LT. In 76% of LT, the cardiovascular burden did not progress after LT. According to our experience and in several other reported cases, the LDL-C levels are slowly increasing over time post LT. Most of the follow-up data were short termed; only a few case reports have followed patients for 10 or more years after LT. LT is a feasible therapeutic option for HoFH patients, reversing atherosclerotic changes uncontrollable by conservative therapy, thus importantly improving the HoFH patient's prognosis and quality of life.

Autoimmune and Inflammatory Manifestations in 247 Patients with Primary Immunodeficiency-a Report from the Slovenian National Registry.

An abnormal regulation of immune responses leads to autoimmune and inflammatory manifestations in patients with primary immunodeficiencies (PIDs). The objective of our study was to evaluate the frequency of non-infectious and non-malignant manifestations in a large cohort of patients included in the Slovenian national PID registry and to assess the time of manifestation onset with respect to the time of PID diagnosis. Medical records of registered patients were reviewed. Data on autoimmunity, lymphoproliferation, autoinflammation, allergies, PID diagnosis, and underlying genetic defects were collected and analyzed. The time of each manifestation onset was determined and compared with the time of PID diagnosis. As of May 2015, 247 patients with 50 different PIDs were registered in the Slovenian national PID registry (147 males, 100 females; mean age 20 years). Mean disease duration was 14 years; 78 % of patients were younger than 18 years; and 22 % of patients were adults. Diagnosis of PID was genetically confirmed in 51 % of patients. Non-infectious and non-malignant manifestations were present in 69/235 (29 %) patients, including autoimmune manifestations in 52/235 (22 %), lymphoproliferative/granulomatous in 28/235 (12 %), autoinflammatory in 12/247 (5 %), and allergic manifestations in 10/235 (4 %) of all registered patients. Autoimmune manifestations were present in all patients whose PIDs were classified as diseases of immune dysregulation, 47 % of patients with chronic granulomatous disease, and 38 % of patients with predominantly antibody immune deficiencies. A high prevalence of non-infectious and non-malignant manifestations among patients in the Slovenian national PID registry suggests common genetic factors of autoimmunity, inflammation, and immunodeficiency. Patients with PID should be routinely screened for autoimmune and inflammatory manifestations at the time of PID diagnosis and during the long-term follow up.

End-Stage Renal Disease in an Infant With Hajdu-Cheney Syndrome.

Hajdu-Cheney syndrome (HJCYS) is a rare, autosomal dominant, skeletal disorder caused by mutations in the NOTCH2 signaling pathway for which genetic testing has recently become available. Renal abnormalities are associated in at least 10% of cases. We present an 8-year-old Caucasian boy, born with multiple dysmorphic features consistent with HJCYS. Imaging of the urinary tract revealed bilateral cystic dysplastic kidneys with associated vesicoureteral reflux. Renal function has been impaired since birth and deteriorated progressively to end-stage renal disease (ESRD) by the age of two and a half years, when peritoneal dialysis was initiated and only recently renal transplantation was performed. Additional congenital abnormalities and multisystem involvement in HJCYS further complicated management, and he developed refractory anemia. Molecular diagnosis was confirmed by identification of a truncating mutation in exon 34 of NOTCH2. Although, renal abnormalities are considered an integral part of the HJCYS, published reports on ESRD are scarce. In those few published cases, where ESRD was recognized, renal failure developed either in late adolescence or adulthood. This is the first report of early ESRD occurring in a child. Patients with HJCYS may need chronic renal replacement therapy even in early childhood. The management of these children can be challenging given the multisystemic manifestations of HJCYS.

Universal Screening for Familial Hypercholesterolemia in Children.

BACKGROUND: Individuals with familial hypercholesterolemia (FH) who are untreated have up to 100-fold elevated risk for cardiovascular complications compared with those who are unaffected. Data for identification of FH with a universal screening for hypercholesterolemia in children are lacking. OBJECTIVES: This study sought genetic identification of FH from a cohort of children with elevated serum total cholesterol (TC) concentration, detected in a national universal screening for hypercholesterolemia. METHODS: Slovenian children born between 1989 and 2009 (n = 272) with TC >6 mmol/l (231.7 mg/dl) or >5 mmol/l (193.1 mg/dl) plus a family history positive for premature cardiovascular complications, identified in a national universal screening for hypercholesterolemia at 5 years of age were genotyped for variants in LDLR, PCSK9, APOB, and APOE. RESULTS: Of the referred children, 57.0% carried disease-causing variants for FH: 38.6% in LDLR, 18.4% in APOB, and none in PCSK9. Nine novel disease-causing variants were identified, 8 in LDLR, and 1 in APOB. Of the remaining participants, 43.6% carried the APOE E4 isoform. Estimated detection rate of FH in the universal screening program from 2009 to 2013 was 53.6% (95% confidence interval [CI]: 34.5% to 72.8%), peaking in 2013 with an upper estimated detection rate of 96.3%. Variants in LDLR, APOB, or the APOE E4 isoform occurred in 48.6%, 60.0%, and 76.5%, respectively, of patients with a family history negative for cardiovascular complications. CONCLUSIONS: Most participants who were referred from a national database of universal screening results for hypercholesterolemia had genetically confirmed FH. Data for family history may not suffice for reliable identification of patients through selective and cascade screening.

Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation.

UNLABELLED: Donohue syndrome (leprechaunism; OMIM *246200) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene (INSR) causing either defects in insulin binding or receptor autophosphorylation and tyrosine kinase activity. We report a patient with pronounced clinical picture of leprechaunism who developed severe progressive hypertrophic obstructive cardiomyopathy (HOCM) and renal tubular dysfunction which improved on continuous subcutaneous infusion of recombinant human insulin-like growth factor-1 (rhIGF-I). INSR gene molecular analysis and insulin receptor (IR) autophosphorylation on cultured fibroblasts were performed. A novel homozygous missense mutation p.Leu795Pro was found, located in the extracellular portion of the ß subunit of the insulin receptor. The post-binding defect of the insulin receptor signaling in cultured fibroblasts demonstrated decreased insulin receptor autophosphorylation. CONCLUSION: Treatment with rhIGF-I partially reversed severe progressive HOCM and renal tubular dysfunction in a patient with Donohue syndrome associated with a novel p.Leu795Pro INSR gene mutation causing a severe decrease in IR autophosphorylation.

Bone mineral density and importance of strict gluten-free diet in children and adolescents with celiac disease.

OBJECTIVES: Low bone mineral density (BMD) is common in children and adolescents with celiac disease. Strict gluten-free diet (GFD) improves bone mineralization, even in 1 year. The effect of occasional gluten intake is not known. The aims of this study were to compare BMD and prevalence of low BMD in children and adolescents on strict and not strict GFD. METHODS: We measured BMD in 55 children and adolescents (strict GFD) with negative endomysium antibodies (EMA) in the last 2 years and in 19 (not strict GFD) with positive EMA at the time of the study. Lumbar, left hip and total body BMD were measured by dual-energy X-ray absorptiometry. Four-day weighted dietary protocols were obtained by means of a self-completed questionnaire of total food and beverage intake. Energy and calcium intake were calculated using nutrition data software. EMA, tissue transglutaminase antibodies, serum calcium, phosphate, 25-hydroxy vitamin D, intact parathormone, albumin, urea and creatinine levels were determined in all patients. RESULTS: BMD in patients on strict GFD was significantly higher than in patients on not strict GFD (lumbar p=0.01; total body p=0.005). There were significantly more patients with total body BMD below -1.0 in not strictly compliant group (71% compared to 38%; p=0.03). Calcium intake and vitamin D levels were below recommendations in both groups. CONCLUSION: Children and adolescents on not strict GFD are at increased risk for low BMD. We therefore recommend that BMD should be evaluated in patients with positive EMA. In addition, patients on strict GFD are at risk for low BMD because of low calcium intake or vitamin D deficiency. Therefore, strict GFD with recommended calcium intake and vitamin D supplementation during winter and spring should be encouraged in all children and adolescents with celiac disease.

Gonadal function in patients treated for Hodgkin's disease in childhood.

BACKGROUND: The long-term survival of patients treated for Hodgkin`s disease (HD) in childhood is high and the chief concern is now being directed toward the late effects of the treatment, including the endocrine dysfunction. PATIENTS AND METHODS.: Testicular and ovarian functions were assessed in 64 long term survivors (24 females, 40 males) treated for HD in childhood in Slovenia between 1972 and 1994. At diagnosis they were 3-16 years old and had gonadal evaluation 4-27 years later at the age of 13-34. Fifty-four (84%) patients received chemotherapy (ChT), 49 in combination with radiation therapy (RT), 10 received RT alone. Gonadal function was assessed by the clinical examination and measurement of serum concentrations of estradiol and testosterone. Serum levels of LH and FSH were determined in the basal state and after the stimulation. RESULTS: Primary hypogonadism (PH) was found in 30 (47%) patients. Twenty-four of 40 (60%) males had PH with evidence of damage of germinal epithelium, 4 of them had evidence of damage of Leydig cells (LC) and 10 had evidence of dysfunction of LC as well. PH was found in 6 of 24 (25%) females. CONCLUSIONS: After therapy for HD PH was more frequent in males than in females. Not only RT but also alkylating agents and procarbazine alone caused damage of LC. Age of patient at the time of treatment was not an important risk factor for gonadal toxicity. Pelvic RT in combination with ChT is the most important risk factor of the development PH both, in males and females.

Gonadal function in patients treated for leukemia in childhood.

Ovarian and testicular function were assessed in 67 long-term survivors (37 females, 30 males) treated for leukemia between 1973 and 1992. At diagnosis they were 1-16 (median 5) years old and had evaluation of gonadal function 4-25 (median 13) years later at the age of 13-31 (median 19). All had been treated with various combinations of chemotherapy (ChT) (including cyclophosphamide (CYC) and cytarabine in 32 patients), 62 patients had received prophylactic cranial irradiation with 12-49 (median 18) Gy, 2 patients had had craniospinal irradiation with 24 and 10 Gy respectively. Nine patients were treated for relapse; 2 boys had testicular irradiation (RT) with 12 Gy in 3 fractions and 1 girl whole-abdomen RT with 20 Gy as a part of this treatment. Three patients were treated for second malignancies. Gonadal function was assessed by clinical examination and measurement of serum concentrations of estradiol and testosterone. Serum levels of LH and FSH were determined in basal state and after stimulation. Primary hypogonadism was found in 6 (9%) patients. Five (16,5%) males had primary hypogonadism with evidence of damage to the germinal epithelium, 2 of them, treated with testicular RT, had evidence of damage to the Leydig cells and 2 had evidence of dysfunction of Leydig cells as well. Primary hypogonadism was found in 1 female, who was heavily treated for relapse (ChT containing CYC, abdominal RT and craniospinal RT). She was amenorrhoic and needed substitutional estrogen therapy but delivered a child anyway. Five females had early puberty after cranial RT. One female had secondary hypogonadism and hyposomatotropism after cranial RT with 30 Gy, one male had hyposomatotropism after receiving cranial RT twice (49 Gy total). Primary treatment for leukemia does not produce primary hypogonadism in girls, but it does in boys. Alkylating agents and gonadal RT are the most damaging factors. Not only RT to gonads but also alkylating agents alone cause dysfunction of Leydig cells.