Rapid response to abatacept in treatment-resistant pansclerotic morphoea.

Morphoea is a spectrum of disorders characterized by inflammation and sclerosis of the skin and potentially underlying tissues. There are no specific licensed treatments for morphoea and prospective studies on commonly used therapies are lacking. We describe a case of progressive, recalcitrant pansclerotic morphoea with a rapid response to abatacept.

New Zealand's extinct giant raptor (Hieraaetus moorei) killed like an eagle, ate like a condor.

The extinct Haast's eagle or harpagornis (Hieraaetus moorei) is the largest known eagle. Historically, it was first considered a predator, then a scavenger, but most recent authors have favoured an active hunting ecology. However, the veracity of proposed similarities to carrion feeders has not been thoroughly tested. To infer feeding capability and behaviour in harpagornis, we used geometric morphometric and finite-element analyses to assess the shape and biomechanical strength of its neurocranium, beak and talons in comparison to five extant scavenging and predatory birds. The neurocranium of harpagornis is vulture-like in shape whereas its beak is eagle-like. The mechanical performance of harpagornis is closer to extant eagles under biting loads but is closest to the Andean condor (Vultur gryphus) under extrinsic loads simulating prey capture and killing. The talons, however, are eagle-like and even for a bird of its size, able to withstand extremely high loads. Results are consistent with the proposition that, unlike living eagles, harpagornis habitually killed prey larger than itself, then applied feeding methods typical of vultures to feed on the large carcasses. Decoupling of the relationship between neurocranium and beak shape may have been linked to rapid evolution.

Locally unresectable differentiated thyroid cancer: outcomes and perspectives.

PURPOSE: Differentiated thyroid cancer (DTC) patients with an unresectable primary tumor cannot benefit from curative surgery, and radioiodine treatment for locoregional and distant disease is not possible with the thyroid gland still in place. Due to local invasion, these patients cannot be included in clinical trials, so that treatment options are limited. The aim of this study was to describe the characteristics and the prognosis of patients with these locally unresectable DTC. PATIENTS AND METHODS: A retrospective and multicentric analysis of consecutive cases of unresectable DTC diagnosed between 2000 and 2015 was performed. RESULTS: The study population consisted in 22 patients, 13 females (59%); median age: 77 years (range: 52-91). Thyroid tumors were papillary in six, follicular in seven, Hürthle cell in one and poorly differentiated in eight patients. Patients were treated with external beam radiation therapy (EBRT) (57%), locoregional therapy of distant metastases (41%), cytotoxic chemotherapy (38%) and tyrosine kinase inhibitors (TKIs) (33%). TKI treatment resulted in median disease control duration of 7 months with a grade 3-4 toxicity rate of 44%. Only one patient had a total thyroidectomy after neo-adjuvant EBRT. The 1, 3 and 5-year cumulative survival rate was 81%, 27.7% and 21.5%, respectively. The cause of death was DTC in 11 cases (local progression in 7), and to other causes in 7 cases; no patient died from treatment toxicity. CONCLUSIONS: Clinical trials and approved treatments are lacking for unresectable DTC. TKI treatment may allow prolonged disease control with acceptable toxicity.

Egg shape mimicry in parasitic cuckoos.

Parasitic cuckoos lay their eggs in nests of host species. Rejection of cuckoo eggs by hosts has led to the evolution of egg mimicry by cuckoos, whereby their eggs mimic the colour and pattern of their host eggs to avoid egg recognition and rejection. There is also evidence of mimicry in egg size in some cuckoo-host systems, but currently it is unknown whether cuckoos can also mimic the egg shape of their hosts. In this study, we test whether there is evidence of mimicry in egg form (shape and size) in three species of Australian cuckoos: the fan-tailed cuckoo Cacomantis flabelliformis, which exploits dome nesting hosts, the brush cuckoo Cacomantis variolosus, which exploits both dome and cup nesting hosts, and the pallid cuckoo Cuculus pallidus, which exploits cup nesting hosts. We found evidence of size mimicry and, for the first time, evidence of egg shape mimicry in two Australian cuckoo species (pallid cuckoo and brush cuckoo). Moreover, cuckoo-host egg similarity was higher for hosts with open nests than for hosts with closed nests. This finding fits well with theory, as it has been suggested that hosts with closed nests have more difficulty recognizing parasitic eggs than open nests, have lower rejection rates and thus exert lower selection for mimicry in cuckoos. This is the first evidence of mimicry in egg shape in a cuckoo-host system, suggesting that mimicry at different levels (size, shape, colour pattern) is evolving in concert. We also confirm the existence of egg size mimicry in cuckoo-host systems.

Pulmonary arterial hypertension - progress in understanding the disease and prioritizing strategies for drug development.

Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease. The breadth and depth of expertise focused on unravelling the molecular pathology of PAH has yielded novel insights, including the role of growth factors, inflammation and metabolic remodelling. The description of the genetic architecture of PAH is accelerating in parallel, with novel variants, such as those reported in potassium two-pore domain channel subfamily K member 3 (KCNK3), adding to the list of more established mutations in genes associated with bone morphogenetic protein receptor type 2 (BMPR2) signalling. These insights have supported a paradigm shift in treatment strategies away from simply addressing the imbalance of vasoactive mediators observed in PAH towards tackling more directly the structural remodelling of the pulmonary vasculature. Here, we summarize the changing clinical and molecular landscape of PAH. We highlight novel drug therapies that are in various stages of clinical development, targeting for example cell proliferation, metabolic, inflammatory/immune and BMPR2 dysfunction, and the challenges around developing these treatments. We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both as potential drug targets and as biomarkers for patient selection. The expectation is that together these will enable the prioritization of potential therapies in development and the evolution of personalized medicine for PAH.

The coexistence of primary hyperparathyroidism and thyroid nodules: should the preoperative work-up of the parathyroid and the thyroid diseases be specifically adjusted?

INTRODUCTION AND OBJECTIVES: Primary hyperparathyroidism (PHPT) can be found in concomitance with thyroid disease (TD) in a high frequency of cases. In this context the diagnostic exams for localizing the enlarged parathyroid(s) gland(s) could be less reliable or nonconclusive. Moreover, the thyroid carcinoma seems to be more frequent compared to that isolated thyroid desease and, therefore, carefully investigated. The main goal of the present study is to evaluate which diagnostic tool (US, MIBI) is more reliable for localizing the site of the PTH hypersecretion and to confirm if it is always advantageous a combination of both exams. Besides, we evaluated the incidence of thyroid carcinoma in our series of patients. PATIENTS AND METHODS: A review of available data of 73 patients who underwent total thyroidectomy + parathyroidectomy from 2003 and 2014 was performed. The preoperative workup included systematically US and MIBI whose results were considered true positive when at least the side (left/right) of the parathyroid affected were concordant with the surgical report, settled as the gold standard, according to the Cox nonnested model. The connection between the diagnostic results of US versus MIBI was calculated with the Cohen K index for evaluating their overlap. The average of the thyroid carcinoma were also calculated. RESULTS: The difference between respectively US versus surgical report (p value=0.73) and MIBI versus surgical report (p value=0.81) were not significant. The low Cohen K index showed that both US and MIBI are complementary. In 23 patients (32,9%) a thyroid carcinoma was found. CONCLUSIONS: The association of MIBI and neck US is mandatory in the first evaluation of patients undergoing thyroidectomy and parathyroid excision simultaneously. The high prevalence of thyroid carcinoma in this specific context suggests a more aggressive diagnostic and surgical behaviour.

Comparison of minimally invasive parathyroidectomy under local anaesthesia and minimally invasive video-assisted parathyroidectomy for primary hyperparathyroidism: a cost analysis.

BACKGROUND: Primary hyperparathyroidism (PHPT) origins from a solitary adenoma in 70- 95% of cases. Moreover, the advances in methods for localizing an abnormal parathyroid gland made minimally invasive techniques more prominent. This study presents a micro-cost analysis of two parathyroidectomy techniques. PATIENTS AND METHODS: 72 consecutive patients who underwent minimally invasive parathyroidectomy, video-assisted (MIVAP, group A, 52 patients) or "open" under local anaesthesia (OMIP, group B, 20 patients) for PHPT were reviewed. Operating room, consumable, anaesthesia, maintenance costs, equipment depreciation and surgeons/anaesthesiologists fees were evaluated. The patient's satisfaction and the rate of conversion to conventional parathyroidectomy were investigated. T-Student's, Kolmogorov-Smirnov tests and Odds Ratio were used for statistical analysis. RESULTS: 1 patient of the group A and 2 of the group B were excluded from the cost analysis because of the conversion to the conventional technique. Concerning the remnant patients, the overall average costs were: for Operative Room, 1186,69 € for the MIVAP group (51 patients) and 836,11 € for the OMIP group (p<0,001); for the Team, 122,93 € (group A) and 90,02 € (group B) (p<0,001); the other operative costs were 1388,32 € (group A) and 928,23 € (group B) (p<0,001). The patient's satisfaction was very strongly in favour of the group B (Odds Ratio 20,5 with a 95% confidence interval). CONCLUSIONS: MIVAP is more expensive compared to the "open" parathyroidectomy under local anaesthesia due to the costs of general anaesthesia and the longer operative time. Moreover, the patients generally prefer the local anaesthesia. Nevertheless, the rate of conversion to the conventional parathyroidectomy was relevant in the group of the local anaesthesia compared to the MIVAP, since the latter allows a four-gland exploration.

Protection of ovarian tissue from radiotherapy.

Advances researches in the diagnosis and treatment of childhood, adolescent and adult cancer have greatly increased the life expectancy of premenopausal women with cancer. However, one of the serious side effects of these treatments is the risk of damage to fertility. The ovaries are very sensitive to cytotoxic and radiotherapeutic treatment. The only established method of fertility preservation is embryo cryopreservation according to the Ethics Committee of the American Society for Reproductive Medicine (2005), but this option requires the patient to be of pubertal age, have a partner or use donor sperm, and be able to undergo a cycle of ovarian stimulation, which is not possible when the radiotherapy has to be initiated immediately or when stimulation is contraindicated according to the type of cancer. For patients who need immediate radiotherapy, cryopreservation of ovarian tissue is the only possible alternative. This manuscript reports the different techniques of cryopreservation and the results of transplantation of cryopreserved ovarian tissue. The current techniques allow cryopreservation of human ovarian fragments for a long time with good follicular survival rate after thawing. Numerous studies ultimately in this field have demonstrated to improve the survival rate of the oocytes and cryopreserved follicles. Moreover this manuscript includes a case of a 17-year-old girl who had to undergo pelvic irradiation for non-Hodgkin's lymphoma and the laparoscopic treatment to preserve the fertility (Fig. 2, Ref. 47).

BRAF(V600E) mutation and the biology of papillary thyroid cancer.

BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.

Co-expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) in thyroid nodules is associated with co-expression of CD30 ligand/CD30 receptor.

Data on the expression of interleukin 6 (IL-6)/interleukin 6 receptor (IL-6R) in thyroid nodules is scarce. Based on our recent data of CD30 ligand (CD30L)/CD30 receptor (CD30) in these nodules and on the knowledge that this signal stimulates IL-6 production in non-thyroid neoplasms, we wanted to evaluate the immunocytochemical expression of these 2 ligand/receptor systems in a large archival series of paraffin-embedded specimens. These specimens included 6 normal thyroids and 130 thyroid nodules. Co-expression of IL-6 and IL-6R in the epithelial (follicular) cells was observed solely in CD30L/CD30 positive nodules: 5/15 (33%) oncocytic adenomas; 6/30 (20%) follicular adenomas which belonged to 2 variants (4/4 microfollicular toxic and 2/2 hyalinizing trabecular); 9/30 (30%) papillary thyroid cancers (PTC), all belonging to the conventional variant. In PTC the proportion of tumor epithelial cells that were IL6 positive was inversely correlated with the pTNM staging (r=-0.549, p=0.01). All 15 follicular cancers (FTC), all 6 anaplastic cancers (ATC) were IL-6/lL-6R negative; 14/15 FTC and 5/6 ATC were CD30L/CD30 negative. In another oncocytic adenoma, another 4 conventional PTC and another 7 non-conventional PTC CD30L/CD30 expression was associated to expression of IL-6 only. IL-6 staining associated to absent expression of CD30L and CD30 was observed in 7 follicular adenomas (all belonging to variants different from toxic and hyalinizing trabecular), 2 oncocytic adenomas, 5 of the 30 colloid nodules and 2 normal thyroids. Of the 6 tumors arising from the parafollicular C cells (medullary thyroid cancer, MTC), all 3 that had metastasized were CD30L/CD30/IL-6 positive and IL-6R negative; only IL-6 expression was lost in both the local and distant metastases. This finding matched the loss of IL-6 expression in one PTC metastasis. All 3 non-metastasized MTC were IL-6/IL-6R negative, and 1/3 was CD30L positive/CD30 negative. We conclude that only in a subset of both benign and malignant thyroid nodules the IL-6/IL-6R signal could be induced by the CD30L/CD30. IL-6 expression is related with aggressiveness in both PTC and MTC. In the normal thyroid tissue, colloid nodules, and another subset of benign and malignant thyroid nodules, IL-6 expression is under control of signals other than CD30L/CD30.

Color Doppler measurement of blood flow in the inferior thyroid artery in patients with autoimmune thyroid diseases.

PURPOSE: The aim of the study is to find out whether the measurement of peak systolic velocity in the inferior thyroid artery (ITA) is a valuable parameter to differentiate autoimmune thyroid diseases (hyper-, normo- or hypofunctional) and to evaluate the efficacy of medical treatment. MATERIAL AND METHODS: The ITA of 31 patients (eight with Graves' disease, 23 with subclinical hypothyroidism) was examined with color Doppler and pulsed Doppler. The final diagnosis was obtained by cytology and by hormonal and antibodies assays. The patients were monitorized by ultrasound for a period of 8 months. RESULTS: In all the patients with Graves' disease the peak systolic velocity was always over 150 cm/s, while in other autoimmune thyroiditis the peak systolic velocity was within the normal range, and never exceeding 65 cm/s. In the first group, the measurement taken in the ITA showed also the efficacy of the pharmacological treatment earlier and more reliably than the color Doppler pattern obtained in the parenchyma. CONCLUSIONS: The color Doppler measurement of the ITA seems to be a promising technique with low-cost and easy approach. In our experience, the color Doppler of the ITA could have a clinical role in the differential diagnosis of diffuse thyroid diseases and in the follow-up of the Graves' disease during medical treatment.

Thyroid carcinosarcoma, a rare and aggressive histotype: a case report.

Thyroid carcinosarcoma is a rare and aggressive thyroid tumor. Histological examination of a tumor showed the characteristic of epithelial carcinoma and mesenchymal differentiation. We retrospectively analyzed the course of the patient and reviewed the literature in which only 19 other cases are described. Carcinosarcoma of the thyroid is a very aggressive tumor with a clinical course similar to anaplastic thyroid carcinoma. Survival is very short despite aggressive multimodal treatment.

Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.

Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused by a defect in the transport of cystine across the lysosomal membrane and characterized by early onset of renal proximal tubular dysfunction. Late-onset cystinosis, a rarer form of the disorder, is characterized by onset of symptoms between 12 and 15 years of age. We previously characterized the cystinosis gene, CTNS, and identified pathogenic mutations in patients with infantile nephropathic cystinosis, including a common, approximately 65 kb deletion which encompasses exons 1-10. Structure predictions suggested that the gene product, cystinosin, is a novel integral lysosomal membrane protein. We now examine the predicted effect of mutations on this model of cystinosin. In this study, we screened patients with infantile nephropathic cystinosis, those with late-onset cystinosis and patients whose phenotype does not fit the classical definitions. We found 23 different mutations in CTNS; 14 are novel mutations. Out of 25 patients with infantile nephropathic cystinosis, 12 have two severely truncating mutations, which is consistent with a loss of functional protein, and 13 have missense or in-frame deletions, which would result in disruption of transmembrane domains and loss of protein function. Mutations found in two late-onset patients affect functionally unimportant regions of cystinosin, which accounts for their milder phenotype. For three patients, the age of onset of cystinosis was <7 years but the course of the disease was milder than the infantile nephropathic form. This suggests that the missense mutations found in these individuals allow production of functional protein and may also indicate regions of cystinosin which are not functionally important.

Quantitative comparison of technetium-99m tetrofosmin and thallium-201 images of the thyroid and abnormal parathyroid glands.

The aim of the study was to quantitatively compare the scintigraphic images of the thyroid and abnormal parathyroid glands obtained with technetium-99m tetrofosmin and thallium-201 in patients with hyperparathyroidism. Forty-six patients with hyperparathyroidism underwent (201)Tl (74 MBq), (99m)Tc-pertechnetate (74 MBq) and (99m)Tc-tetrofosmin (555-740 MBq) scintigraphy in a single session. Image analysis included the computation of the thyroid/background ratio in the whole study population and the parathyroid/background ratio, parathyroid/thyroid ratio and diagnostic sensitivity in 17 patients who underwent parathyroid surgery. The pertechnetate subtraction technique was used. (201)Tl and (99m)Tc-tetrofosmin showed a similar thyroid/background ratio (1.79+/-0.41 and 1.81+/-0. 47, respectively, P=NS); however, (99m)Tc-tetrofosmin showed a higher parathyroid/background ratio than (201)Tl (2.06+/-0.54 vs 1. 79+/- 0.50, P=0.007). Despite the superior quality of (99m)Tc-tetrofosmin images, both tracers showed identical sensitivity in detecting enlarged parathyroid glands in patients with primary hyperparathyroidism (89%) and in those with secondary hyperparathyroidism (50%).

Molecular characterization of CTNS deletions in nephropathic cystinosis: development of a PCR-based detection assay.

Nephropathic cystinosis is an autosomal recessive disorder that is characterized by accumulation of intralysosomal cystine and is caused by a defect in the transport of cystine across the lysosomal membrane. Using a positional cloning strategy, we recently cloned the causative gene, CTNS, and identified pathogenic mutations, including deletions, that span the cystinosis locus. Two types of deletions were detected-one of 9.5-16 kb, which was seen in a single family, and one of approximately 65 kb, which is the most frequent mutation found in the homozygous state in nearly one-third of cystinotic individuals. We present here characterization of the deletion breakpoints and demonstrate that, although both deletions occur in regions of repetitive sequences, they are the result of nonhomologous recombination. This type of mechanism suggests that the approximately 65-kb deletion is not a recurrent mutation, and our results confirm that it is identical in all patients. Haplotype analysis shows that this large deletion is due to a founder effect that occurred in a white individual and that probably arose in the middle of the first millenium. We also describe a rapid PCR-based assay that will accurately detect both homozygous and heterozygous deletions, and we use it to show that the approximately 65-kb deletion is present in either the homozygous or the heterozygous state in 76% of cystinotic patients of European origin.

Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC.

Structure of the human sarco/endoplasmic reticulum Ca2+-ATPase 3 gene. Promoter analysis and alternative splicing of the SERCA3 pre-mRNA.

Human chromosome 17-specific genomic clones extending over 90 kilobases (kb) of DNA and coding for sarco/endoplasmic reticulum Ca2+-ATPase 3 (SERCA3) were isolated. The presence of the D17S1828 genetic marker in the cosmid contig enabled us to map the SERCA3 gene (ATP2A3) 11 centimorgans from the top of the short arm p of chromosome 17, in the vicinity of the cystinosis gene locus. The SERCA3 gene contains 22 exons spread over 50 kb of genomic DNA. The exon/intron boundaries are well conserved between human SERCA3 and SERCA1 genes, except for the junction between exons 8 and 9 which is found in the SERCA1 gene but not in SERCA3 and SERCA2 genes. The transcription start site (+1) is located 152 nucleotides (nt) upstream of the AUG codon. The 5'-flanking region, including exon 1, is embedded in a 1.5-kb CpG island and is characterized by the absence of a TATA box and by the presence of 14 putative Sp1 sites, 11 CACCC boxes, 5 AP-2-binding motifs, 3 GGCTGGGG motifs, 3 CANNTG boxes, a GATA motif, as well as single sites for Ets-1, c-Myc, and TFIIIc. Functional promoter analysis indicated that the GC-rich region (87% G + C) from -135 to -31 is of critical importance in initiating SERCA3 gene transcription in Jurkat cells. Exon 21 (human, 101 base pairs; mouse, 86 base pairs) can be alternatively excluded, partially included, or totally included, thus generating, respectively, SERCA3a (human and mouse, 999 amino acids (aa)), SERCA3b (human, 1043 aa; mouse, 1038 aa), or SERCA3c (human, 1024 aa; mouse, 1021 aa) isoforms with different C termini. Expression of the mouse SERCA3 isoforms in COS-1 cells demonstrated their ability to function as active pumps, although with different apparent affinities for Ca2+.

A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis.

Nephropathic cystinosis, an autosomal recessive disorder resulting from defective lysosomal transport of cystine, is the most common inherited cause of renal Fanconi syndrome. The cystinosis gene has been mapped to chromosome 17p13. We found that the locus D17S829 was homozygously deleted in 23 out of 70 patients, and identified a novel gene, CTNS, which mapped to the deletion interval. CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. Eleven different mutations, all predicted to cause loss of function of the protein, were found to segregate with the disorder.