We report the clinical and molecular characteristics of 12 Spanish families with multiple members affected with Lé ri-Weill dyschondrosteosis (LWD) or Langer mesomelic dysplasia (LMD), who present the SHOX (short stature homeobox gene) mutation p.A170P (c.508G4C) in heterozygosity or homozygosity, respectively. In all studied families, the A170P mutation co-segregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. A shared haplotype around SHOX was observed by microsatellite analysis, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the families were of this ethnic group. Mutation screening in 359 Eastern-European Gypsies failed to identify any carriers. For the first time, we have shown SHOX expression in the human growth plate of a 22-week LMD fetus, homozygous for the A170P mutation. Although the mutant SHOX protein was expressed in all zones of the growth plate, the chondrocyte columns in the proliferative zone were disorganized with the chondrocytes occurring in smaller columnal clusters. We have also identified a novel mutation at the same residue, c. 509C4A (p.A170D), in two unrelated Spanish LWD families, which similar to A170P mutation impedes nuclear localization of SHOX. In conclusion, we have identified A170P as the first frequent SHOX mutation in Gypsy LWD and LMD individuals.

Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia associated with pain and stiffness of multiple joints, enlargement of the interphalangeal joints, normal inflammatory parameters, and absence of extra-skeletal manifestations. Homozygous or compound heterozygous WISP3 mutations cause PPD. We report two siblings from a non-consanguineous Ecuadorian family with a late-onset spondyloepiphyseal dysplasia. Mutation screening was undertaken in the two affected siblings using a customized skeletal dysplasia next generation sequencing (NGS) panel and confirmed by Sanger sequencing. Two compound heterozygous mutations were identified in WISP3 exon 2, c.[190G>A];[197G>A] (p.[(Gly64Arg)];[(Ser66Asn)]) in the two siblings, both of which had been inherited. The p. (Gly64Arg) mutation has not been previously described whilst the p. (Ser66Asn) mutation has been reported in two PPD families. The two siblings presented with atypical PPD, as they presented during late childhood, yet the severity was different between them. The progression was particularly aggressive in the male sibling who suffered severe scoliosis by the age of 13 years. This case reaffirms the clinical heterogeneity of this disorder and the clinical utility of NGS to genetically diagnose skeletal dysplasias, enabling adequate management, monitorization, and genetic counseling. © 2016 Wiley Periodicals, Inc.

INTRODUCTION The thyroglossal duct cyst (TGDC) is the most common congenital anomaly of the neck in childhood. However, thyroid carcinoma of the thyroglossal duct cyst is rare. It occurs in less than 1% of cases and the diagnosis is usually made from histopathologic findings after cyst surgery. Papillary carcinoma is the most common histologic subtype. The management of the TGDC carcinoma is not well defined. Sistrunk procedure (resection of the cyst and hyoid bone) followed by total thyroidectomy is the classic treatment, due to frequency of concomitant thyroid cancer (20-60%). However some authors propose a more conservative management performing thyroidectomy only in certain cases (positive margins, abnormal preoperative imaging, extension of TGDC carcinoma beyond the cyst wall). Lymph node resection and radioactive iodine therapy are used on advanced stages. CLINICAL CASE A 12-year-old boy presented with a four-month history of neck swelling. There was no previous exposure to irradiation or positive family history of thyroid cancer. Physical examination revealed a 5 cm mass located in the midline region of the neck, slightly tilted to the left, above the hyoid bone, covered by normal skin. A neck ultrasound was performed showing a normal thyroid gland, and a cystic lesión compatible with a TGDC. A CT scan corroborated this finding, showing a cystic lesión of about 3.1 cm x 2.1 cm x 3.7 cm (anteroposterior, transverse and craniocaudal planes) with a small solid pole in the posterior portion of the cyst, 1x1 cm on the axial plane. Small cervical lymph nodes with no suspicious features were also described. Thyroid function tests were normal. Sistrunk operation was performed for resection of the TGDC. Histologic examination revealed papillary carcinoma in a thyroglossal duct cyst. It measured 17 mm at its maximal diameter and invaded the cyst wall 1 mm with negative margins. Consequent to the diagnosis of TGDC carcinoma, total thyroidectomy was performed on a second surgery whithout side effects. Thyroid tissue showed usual morphological features without signs of malignancy. Currently the patient undergoes levothyroxine replacement treatment.CONCLUSIONS Papillary thyroid carcinoma in thyroglossal duct cysts is rare entity and even rare in children. Given that several studies in adults show a non-negligible percentage of patients with TGDC carcinoma and a normal thyroid ultrasound who had a concomitant thyroid cancer, the most controversial part of its management is whether total thyroidectomy should be done or not. Although some groups advocate thyroidectomy only in specific cases of TGDC carcinoma, its multifocal nature and the low risk of complications of thyroid surgery in pediatric referral centers make us supporters of performing total thyroidectomy to all patients.