and Royal Victoria Infirmary (R.Q.), Newcastle-upon Tyne NE1 4LP, United Kingdom Context:The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening.Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects:Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/ PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures:Reproductive and nonreproductive phenotypes within each genetic group were measured. Results:Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 Ϯ 0.1 mL vs 3.7 Ϯ 0.3 mL, P Ͻ .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P Ͻ .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P Ͻ .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P Ͻ .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions:Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening. (J Clin Endocrinol Metab 98: E943-E953, 2013)

Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.heparan sulfotransferase | Kallmann syndrome T he coordinated assembly of the nervous system in metazoans requires the migration of the large majority of neurons from their place of origin to their final destination in the brain (1). These processes require the complex interplay of many factors, including secreted and transmembrane proteins that mediate communication between cells. The activity of such factors is greatly influenced by the extracellular environment (2). For example, heparan sulfates (HSs), a class of molecularly diverse extracellular glycosaminoglycans, have been shown to be crucial for neural development in mice (3). From work in model organisms, it has become clear that much of the function of HS during neural development is embedded within complex modification patterns of the HS sugar residues (reviewed in refs. 4 and 5). HS modification patterns serve specific and instructive functions during neural development and are believed to regulate ligand-receptor interactions (6-8). These patterns arise as the consequence of nonuniform modifications of the sugar moieties, including sulfations, deacetylations, and epimerizations that are introduced by specific HS-modifying enzymes (9) (Fig. 1A). It is unknown whether the function of HS modifications impinges on normal human development and disease susceptibility.Idiopathic hypogonadotropic hypogonadism (IHH) is a clinically and genetically heterogeneous condition that is characterized by lack of sexual maturation and infertility in the absence of other organic etiologies (10). Patients with IHH either have a normal sense of smell [normosmic IHH (nIHH)] or have an impaired sense of smell (anosmia

A computer-based algorithm classified foreign-born status in a large HIV-infected cohort efficiently and accurately. This approach can be used to improve EMR-based outcomes research.

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We present the first case of a term pregnancy following a fertility-preserving procedure (modified Strassman procedure; MSP) to treat a placental site trophoblastic tumour (PSTT). The woman has given written permission for the case to be reported. A 34-year-old white British woman presented in August 2006 as a nulliparous female with an elevated human chorionic gonadotrophin (b-hCG; 350 000 iu) following a scan at 11 weeks of gestation which diagnosed a molar pregnancy. She had no previous medical history or personal or family history of gestational trophoblastic disease (GTD). After uterine evacuation b-hCG was 16 000 iu. Histology of the evacuated tissue was consistent with a partial mole. Doppler ultrasonography showed a 3.7-cm round, mixed echogenic mass lying centrally within the uterine fundus, with increased vascularity at the periphery. The right ovary contained a dermoid cyst and the left ovary was normal. A chest X-ray showed no metastases. She was commenced on 'low-risk' chemotherapy treatment (methotrexate) a month later, which rapidly decreased the b-hCG levels as well as the size of the lesion. A second course of chemotherapy ('high-risk') followed in 2007 secondary to a relapse, with b-hCG levels normalising within 2 months. Unfortunately she relapsed for the second time in May 2008. An ultrasound scan revealed a lesion that was 1.2 cm in size, of abnormal vascularity and reduced Doppler flow and just to the right of the midline. Magnetic resonance imaging confirmed a 1.2-cm focus in the anterior uterine fundus. Following a hysteroscopy and use of a resectoscope, histology revealed that the focus was consistent with a PSTT, with one margin involved in the trophoblastic tumour itself. Subsequently, the lesion was resected using MSP, with uterine reconstruction. Intraoperative ultrasound with aqua flotation was applied to locate the tumour before making the necessary excision. All lymph nodes (34 in total) were tumour free. Clear histological margins were demonstrated on frozen section.Modified Strassman procedure has been described extensively in a previous BJOG publication by Saso et al. 1 Below is a summary of the procedure as undergone by the woman reported here. She had given consent for a low transverse muscle-cutting laparotomy with MSP and pelvic/para-aortic lymph node sampling. A low transverse muscle-cutting incision was used with ligation of the inferior epigastric vessels. On entering the abdomen a normal-sized uterus was seen and the placental nodule was palpable deep within the uterus at the site shown on the scan. The free peritoneal fluid was sucked up and sent for cytopathology. The left ovary had a small haemorrhagic cyst. The right ovary had some minor adhesions, which released. Following opening of the broad ligaments, a Foley catheter was placed around the uterine vessels to temporarily occlude the uterine arterial supply, so permitting uterine isolation. This involves feeding the catheter under the round ligament through perforations created in the peritoneum. Diathermy and tr...

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