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

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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.