High bone mass due to novel LRP5 and AMER1 mutations.

WNT signaling is a key regulator of bone metabolism and its increased or decreased activity leads to skeletal disorders. Here we describe two patients with high bone mass (HBM) caused by novel mutations in two different WNT pathway components. The first patient is a 53-year-old male with HBM. He was diagnosed at adult age based on significantly increased bone mineral density (BMD). He has undergone several surgeries due to excessive bone in ear canals, bilateral jaw exostoses and mandibular tori. Radiographs show severe cortical thickening of cranial and long bones. Sanger sequencing identified a novel heterozygous mutation c.592A>T (p.N198Y) in LRP5 (Low-density lipoprotein receptor-related protein 5). The second patient, an adolescent female, was diagnosed with skeletal dysplasia in early childhood. She had macrocephaly (head circumference +6.0 SD), facial dysmorphism, delayed motor development, laryngomalasia and epilepsy. Radiographic findings were consistent with osteopathia striata with cranial sclerosis. A novel heterozygous frameshift mutation c.655del (p.E219Rfs*63) in AMER1 (APC Membrane Recruiting Protein 1) was identified. Although both mutations are predicted to lead to increased WNT signaling with a consequent increase in bone formation, the resulting phenotypes are different; cranial sclerosis versus macrocephaly, long bone cortical thickening versus vertical striations and discordant neurological development. This report underscores the diversity of genotypes and phenotypes of HBM and facilitates their differential diagnosis.

A nationwide study on parathyroid carcinoma.

BACKGROUND: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing. MATERIAL AND METHODS: We performed a nationwide study on all cases (n= 32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955-1999 was compared to that in 2000-2013. RESULTS: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 µmol/l, p < .001, respectively). Calcium was ≤1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2-13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52-2.14) to 7.14 (range 3.42-10.38)/10.000.000/years; (p < .001). CONCLUSIONS: PC associates with severe primary hyperparathyroidism and must be suspected if calcium ≥1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades.

Pregnancy planning in type 1 diabetic women improves glycemic control and pregnancy outcomes.

OBJECTIVE: Pregnancy in women with type 1 diabetes is associated with increased risks. The aim of this study was to evaluate the effect of pregnancy planning on outcomes of type 1 diabetic pregnancies. METHODS: We retrospectively assessed pregnancy outcomes of type 1 diabetic women who were patients of Diabetes Clinic of North Karelia hospital between 2000 and 2012. We evaluated the medical records of 73 women experiencing 145 pregnancies and data of their infants. RESULTS: Altogether 96 (66.2%) pregnancies were planned. HbA1c levels were significantly lower before and during the whole pregnancy when pregnancy was planned than if it was not planned (all p <0.001). Planned pregnancies resulted in significantly fewer congenital anomalies (p <0.001). Pregnancy planning reduced the age-adjusted risk of Cesarean sections (OR 0.25, p = 0.021). Pregnancy planning was associated with a reduced risk of adverse pregnancy outcomes (including miscarriages and congenital anomalies). This association was independent of age, HbA1c before pregnancy, smoking, hypertension, microvascular complications, and thyroid disease (OR 0.26; 95% CI 0.09, 0.76). CONCLUSIONS: Pregnancy planning is beneficial for glycemic control and pregnancy outcomes of type 1 diabetic women. The benefit of pregnancy planning was independent of other risk factors for adverse pregnancy outcomes.

Health-related quality of life in elderly patients with familial hypercholesterolemia.

OBJECTIVES: There are very few descriptions on how familial hypercholesterolemia (FH), a genetic disorder with an increased risk of coronary heart disease (CHD), affects older patients. The aim of this study was to analyze the health-related quality of life (HRQoL) of elderly patients with FH. METHODS: All FH patients with the same FH North Karelia-mutation aged 65 and over living in North Karelia province in Eastern Finland were asked to participate in the study in 2003. They were compared with age-standardized controls from the Finnish general population. A total of forty-three elderly FH patients were identified and thirty-seven of them (aged 65 to 84 years, M/F 10/27) agreed to participate. Most of them (27/37) had been diagnosed with CHD. All but one of these FH patients had been using statins for approximately 15 years. HRQoL was assessed with the RAND-36 (SF-36) and 15D instruments. RESULTS: Despite the clear cardiovascular morbidity and low socioeconomic status, these FH patients enjoyed a similar HRQoL as the age-standardized controls in the general population. CONCLUSIONS: Lifelong hypercholesterolemia was not associated with poorer HRQoL in elderly survivors of FH. These elderly FH individuals were characterized by their healthy lifestyle and long-term statin treatment.