Familial isolated primary hyperparathyroidism associated with vitamin D deficiency

Abstracts / Bone 47 (2010) S29–S52

caused by a mutation within the GS rich domain. This suggests that although mutations affecting this region cause perturbations in FKBP12 binding, the degree to which binding is affected varies, leading to clinical phenotypes with a range of severity.

Disclosure of Interest: None declared.

Keywords: ACVR1, Fibrodysplasia Ossificans Progressiva (FOP)

doi:10.1016/j.bone.2010.04.615

CC02 Identification of two novel WTX mutations in osteopathia striata with cranial sclerosis patients B. Perdu⁎1, P. Lakeman2, A. Lachmeijer2, R. Koenig3, W. Van Hul1 1 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 2 Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands 3 Institute of Human Genetics Frankfurt, Children’s Hospital, Mainz, Germany Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition marked by linear striations mainly affecting the metaphyseal region of the long bones and pelvis in combination with cranial sclerosis. Recently, the disease causing gene was identified as the WTX gene (FAM123B), an inhibitor of WNT signalling (Jenkins et al. Nat Genet 2009 41(1):95-100). This condition is lethal in most affected males, especially when the mutation resides early in the WTX gene (Perdu et al. JBMR in press). Mutation analysis on individuals of two unrelated families diagnosed with OSCS revealed two novel point mutations. A female patient diagnosed with OSCS showed frontal bossing, hypertelorism, high arched palate, hearing deficit and learning difficulties. Radiographs showed cranial sclerosis, thick calvarium and metaphyseal striations on the long bones. Antenatal ultrasound at 20 weeks into her second pregnancy demonstrated a fetus with bilateral absence of the fibula, macrocephaly, heart defects and intestinal malrotation. The pregnancy was terminated. Mutation analysis of the single coding exon of WTX resulted in the identification of a novel point mutation: c.del654G. This mutation causes a frameshift and leads to an early stop codon. The second patient is the first child of unrelated parents. This male is severely affected and shows almost all typical OSCS features but no striations on his long bones were observed. His mother, off whom Xrays are unavailable, is only mildly affected. Sequence analysis of the WTX gene revealed a previously unknown WTX mutation (c.429T>A) in the young patient. His survival is remarkable because the mutation leads to a very short truncated protein (C143X). His mother showed heterozygozity for this mutation. These two mutations clearly confirm the causality of WTX mutations in the pathogenesis of OSCS. The second family also underlines the unpredictability of male survival while the absence of striations in this male patient suggests that WTX mutations should be considered in cases of cranial sclerosis, even if striations are not present. First two authors made equal contribution.

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CC03 Familial isolated primary hyperparathyroidism associated with vitamin D deficiency R.A. Trifanescu1,2, M. Carsote1, I. Gherlan2, E. Neacsu3, B. Stanescu4,5, D. Ioachim6, D. Hortopan7, C. Poiana⁎1,2 1 Endocrinology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania 2 Endocrinology, "C.I.Parhon" Institute of Endocrinology, Bucharest, Romania 3 Bone Markers, "C.I.Parhon" Institute of Endocrinology, Bucharest, Romania 4 Endocrine Surgery, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania 5 Endocrine Surgery, "C.I.Parhon" Institute of Endocrinology, Bucharest, Romania 6 Pathology, "C.I.Parhon" Institute of Endocrinology, Bucharest, Romania 7 Radiology, "C.I.Parhon" Institute of Endocrinology, Bucharest, Romania Background: Familial hyperparathyroidism may occur as familial isolated hyperparathyroidism or as part of an inherited syndrome, in particular multiple endocrine neoplasia types 1 and 2A and hyperparathyroidism-jaw tumor syndrome. Aim: To present a family with 2 sisters with familial isolated primary hyperparathyroidism and vitamin D deficiency. Methods: Serum intact PTH and 25 OH vitamin D concentration were measured by ELISA. Case reports: The index case, B.C, female, 56 years old, presented with multiple fractures history, bilateral nephrolithiasis. Biochemical data revealed primary hyperparathyroidism (serum total calcium = 11.9 mg/dL, phosphorus = 2.62 mg/dL, PTH = 821.3 pg/mL) and vitamin D deficit (25OH vitamin D = 11.7 ng/mL). Bone turnover markers were marked increased (β crosslaps = 10.1 ng/mL, osteocalcin=1045.6 ng/mL, alkaline phosphatase = 538.2 IU/L), as cromogranine A (706 ng/mL). Secondary osteoporosis was diagnosed: L2–L4 BMD=0.76g/ cm2, T score = −3.6 SD, Z score = −2.9 SD. Cervical ultrasound revealed 3.9/2.2 cm left-inferior parathyroid nodule, with macrocalcifications and CT scan confirmed the localization. A parathyroid tumor was successfully removed; pathology revealed parathyroid adenoma with squamous metaplasia. Calcium, vitamin D and ibandronate were administered. I.D., female, aged 53, sister of B.C., initially showed apparent asymptomatic hypercalcaemia. Endocrine assessment revealed mild primary hyperparathyroidism (serum total calcium = 11.3 mg/dL, phosphorus = 3.3 mg/dL, PTH = 55.13 pg/mL) and vitamin D deficit (25OH vitamin D = 11.11 ng/mL). Secondary osteoporosis was diagnosed: L2–L4 BMD = 0.79 g/cm2, T score = −3.4 SD, Z score = −2.8 SD. Cervical ultrasound, computed tomography scan and 99m Technetium Sestamibi scan failed to localize a parathyroid nodule. Sustained oral hydration and intravenous ibandronate every 3 months successfully controlled hypercalcaemia. Screening for pheochromocytoma and medullary thyroid carcinoma was negative in both cases and there was no family history suggestive for MEN 1 syndrome. Calcium/ creatinine clearance ratio was suggestive for primary hyperparathyroidism. Genetics testing is pending. Conclusion: A familial screening for primary hyperparathyroidism is desirable in cases with onset below 60 years.

Disclosure of Interest: None declared.

Disclosure of Interest: None declared.

Keywords: male survival, novel mutations, osteopathia striata with cranial sclerosis

Keywords: primary hyperparathyroidism, secondary osteoporosis, vitamin D deficiency

doi:10.1016/j.bone.2010.04.616

doi:10.1016/j.bone.2010.04.617