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PubMed1998

A recurrent missense mutation in the KAL gene in patients with X-linked Kallmann's syndrome.

Kallmann's syndrome (KS) is defined by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. Segregation analysis in familial cases has demonstrated diverse inheritance patterns, suggesting the existence of several genes regulating GnRH secretion. Genetic defects have been demonstrated in the KAL gene, located on the Xp22.3 region, explaining the X-linked form of the disease. We report molecular findings regarding the KAL gene in 12 unrelated males with X-linked KS. PCR of the 14 exons of the KAL gene was performed on genomic DNA. PCR products of all exons were purified and sequenced. Genetic defects in the KAL gene were found in 7 patients. One exhibits a deletion from exon 3 to exon 5. Six individuals present a previously unidentified missense mutation in exon 11, consisting of a G to A substitution at codon 514 (GAA to AAA). In the remaining 5 individuals, no mutations were observed. We also found three different polymorphic changes. The first one, in exon 2, had not been reported previously. The other two were located at exons 11 and 12. The deletion described, comprises only part (exon 5) of the coding region of the first fibronectin type III-like repeat of the KAL protein. The rest of the deletion comprises part of the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif. The same missense mutation was found in 6 of the 12 patients, indicating the possibility that it derived from a common ancestor or suggesting the presence of a hot spot in this region of the gene.

Adolescent↗

PubMed2001

Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism.

Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive IHH. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and two had homozygous mutations. Of the eight DNA sequence changes identified, four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266)Arg, and Cys(279)TYR: COS-7 cells transiently transfected with complementary DNAs encoding the human GNRHR containing each of these four novel mutations failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutations is much broader than originally anticipated; 2) the frequency of GNRHR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutations of the GNRHR are distributed widely throughout the protein.

Amino Acid Sequence↗

PubMed2002

The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism.

As our knowledge of the molecular mechanisms underlying idiopathic hypogonadotropic hypogonadism (IHH) expands, it becomes increasingly important to define the phenotypic spectrum of IHH. In this study we examined historical, clinical, biochemical, histological, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. We hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome (KS; IHH with anosmia), 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, KS represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Comparing IHH patients according to the absence (68%) or presence (24%) of some prior pubertal development revealed significant differences in testicular size (3.3 +/- 0.2 vs. 11.8 +/- 1.2 ml; P < 0.001), incidence of cryptorchidism (40% vs. 5%; P < 0.05), microphallus (21% vs. 0%; P < 0.05), inhibin B levels (45 +/- 4 vs. 144 +/- 20 pg/ml; P < 0.0001), and Mullerian inhibitory substance levels (9.8 +/- 1.4 vs. 2 +/- 0.5 ng/ml). Most familial cases had no pubertal development (95% vs. 5%; P < 0.001); males with mutations in the KAL gene displayed the most severe phenotype. Mean gonadotropins levels (LH, 1.8 +/- 0.1 vs. 2.9 +/- 0.4 IU/liter; FSH, 2.2 +/- 0.2 vs. 3.3 +/- 0.3 IU/liter; P < 0.05) and the finding of apulsatile LH secretion based on frequent sampling (80% vs. 55%; P < 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism, and microphallus), biochemical markers of testicular growth and differentiation (inhibin B and Mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. Viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability.

Adult↗

PubMed2002

Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome.

Kallmann's syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. Genetic defects have been observed throughout the KAL1 gene, located on the Xp22.3 region, in less than 50% of the patients. We report the molecular study of the KAL1 gene in 12 males with KS. PCR of the 14 exons of the KAL1 gene was performed on genomic DNA. PCR products of all exons were purified and sequenced. Three novel genetic defects were found. One patient exhibited a complete deletion of exon 5. The second presented a duplication of nucleotides 158-168; this insertion causes a termination codon (TGA) within the same exon. The third presented a mutation in exon 6, in which codon 262 changes from arginine to a stop codon. In the remaining nine individuals, no mutations were found. Three previously reported polymorphic changes were also documented. The deletion of exon 5 occurs within the region encoding the first fibronectin type III-like repeat of the KAL1 protein, this being the first KS patient who exhibits a complete deletion of a single exon of the KAL1 gene. The duplication of nucleotides in exon 1 is located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or stopping the translation at the stop codon. The last novel mutation, a stop codon in exon 6, is located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein. The absence of mutations in the majority of patients suggests the possibility of the existence of other genes involved or that in certain individuals the presence of various polymorphisms within the KAL1 gene could predispose to disease, as has been demonstrated in other pathological entities.

Adolescent↗

PubMed1988

Familial 'sleep apnea plus' syndrome: report of a family.

We describe a familial disorder consisting of sleep apnea, anosmia, colorblindness, partial complex seizures, and cognitive dysfunction. The phenotypic expression of the syndrome suggests an autosomal dominant inheritance with incomplete penetrance.

Adult↗

PubMed1989

Neurologic findings in men with isolated hypogonadotropic hypogonadism.

We studied the neurologic abnormalities in 41 men with isolated hypogonadotropic hypogonadism. Findings included anosmia, hyposmia, mirror movements, ocular motor abnormalities, cerebellar dysfunction, and pes cavus foot deformity. One-third of the subjects had a family history of delayed sexual maturation. Patients with a family history of delayed sexual maturation had a significantly higher incidence of olfactory dysfunction, mirror movements, and pes cavus foot deformity. Our data suggest that isolated hypogonadotropic hypogonadism and its accompanying neurologic abnormalities may arise from a genetically linked developmental abnormality of CNS structures.

Adult↗

PubMed1999

Superficial siderosis of the central nervous system: a late complication of cerebellar tumors.

OBJECTIVE: To describe the clinical and radiologic features of superficial siderosis of the CNS after treatment of a cerebellar tumor. METHODS: Clinical assessment and MRI in four patients with superficial siderosis were performed. RESULTS: Four patients with superficial siderosis had been treated for a primary cerebellar tumor (astrocytoma in three patients, medulloblastoma in one patient) during childhood. All patients were treated with surgery and three received radiotherapy. Slowly progressive bilateral sensorineural hearing loss, gait ataxia, and limb ataxia appeared 8 to 22 years after diagnosis of the cerebellar tumor. Other clinical features were mild cognitive impairment, dysarthria, nystagmus, optic neuropathy, anosmia, and upper motor neuron signs. The CSF contained erythrocytes and increased protein. MRI with fast spin-echo T2-weighted and gradient-echo T2* sequences showed a hypointense rim of iron coating the surface of the cerebellum and brainstem. Twenty-one other patients who had survived more than 5 years after treatment of a primary cerebellar tumor did not have symptoms or signs suggestive of superficial siderosis. CONCLUSIONS: Superficial siderosis is an uncommon late complication of the treatment of a childhood cerebellar tumor, but it is probably underrecognized. The diagnosis should be suspected in patients who present with slowly progressive sensorineural hearing loss and ataxia many years after eradication of a childhood cerebellar tumor.

Adolescent↗

PubMed2005

Olfactory groove meningiomas from neurosurgical and ear, nose, and throat perspectives: approaches, techniques, and outcomes.

OBJECTIVE: To review the surgical approaches, techniques, outcomes, and recurrence rates in a series of 80 olfactory groove meningioma (OGM) patients operated on between 1990 and 2003. METHODS: Eighty patients underwent 81 OGM surgeries. Tumor diameter varied from 2 to 9 cm (average, 4.6 cm). In 35 surgeries (43.2%), the tumor was removed through bifrontal craniotomy; nine operations (11.1%) were performed through a unilateral subfrontal approach; 18 surgeries (22.2%) were performed through a pterional approach; seven surgeries (8.6%) were carried out using a fronto-orbital craniotomy; and 12 procedures (14.8%) were accomplished via a subcranial approach. Nine patients (11.3%) had undergone surgery previously and had recurrent tumor. RESULTS: Total removal was obtained in 72 patients (90.0%); subtotal removal was achieved in 8 patients (10.0%). Two patients, one with total and one with subtotal removal, had atypical (World Health Organization Grade II) meningiomas, whereas 78 patients had World Health Organization Grade I tumors. There was no operative mortality and no new permanent focal neurological deficit besides anosmia. Twenty-five patients (31.3%) experienced surgery-related complications. There were no recurrences in 75 patients (93.8%) 6 to 164 months (mean, 70.8 mo) after surgery. Three patients (3.8%) were lost to follow-up. In two patients (2.5%) with subtotal removal, the residual evidenced growth on computed tomography and/or magnetic resonance imaging 1 year after surgery. One of them had an atypical meningioma. The second, a multiple meningiomata patient, was operated on twice in this series. CONCLUSION: A variety of surgical approaches are used for OGM resection. An approach tailored to the tumor's size, location, and extension, combined with modern microsurgical cranial base techniques, allows full OGM removal with minimal permanent morbidity, excellent neurological outcome, and very low recurrence rates.

Adolescent↗

PubMed2002

The Kallmann syndrome gene homolog in C. elegans is involved in epidermal morphogenesis and neurite branching.

Kallmann syndrome is an inherited disorder defined by the association of anosmia and hypogonadism, owing to impaired targeting and migration of olfactory axons and gonadotropin-releasing hormone secreting neurons. The gene responsible for the X-linked form of Kallmann syndrome, KAL-1, encodes a secreted protein of still elusive function. It has been proposed that KAL-1 might be involved in some aspects of olfactory axon guidance. However, the unavailability of a mouse model, and the difficulties in studying cellular and axonal migration in vertebrates have hampered an understanding of its function. We have identified the C. elegans homolog, kal-1, and document its function in vivo. We show that kal-1 is part of a mechanism by which neurons influence migration and adhesion of epidermal cells undergoing morphogenesis during ventral enclosure and male tail formation. We also show that kal-1 affects neurite outgrowth in vivo by modulating branching. Finally, we find that human KAL-1 cDNA can compensate for the loss of worm kal-1 and that overexpression of worm or human KAL-1 cDNAs in the nematode results in the same phenotypes. These data indicate functional conservation between the human and nematode proteins and establish C. elegans as a powerful animal in which to investigate KAL function in vivo. Our findings add a new player to the set of molecules, which appear to underlie both morphogenesis and axonal/neuronal navigation in vertebrates and invertebrates.

Amino Acid Sequence↗

PubMed1998

The importance of atmospheric odours for the homing performance of pigeons in the sonoran desert of the southwestern united states

The importance of atmospheric odours for homing pigeon navigation in a desert environment was tested using birds from two lofts located in the Sonoran desert near Tucson, Arizona, USA. When released from a familiar training site, experienced control pigeons and pigeons given intranasal injections of zinc sulphate to produce anosmia both displayed good homeward orientation and homed rapidly. When released from two unfamiliar locations, in contrast, the controls continued to display good homing performance while the zinc-sulphate-treated pigeons homed poorly. Significant differences in vanishing bearings, homing time and homing success were recorded. When a group of control and a group of zinc-sulphate-treated inexperienced pigeons were released from two unfamiliar locations, both groups homed poorly. Nonetheless, the controls still outperformed the zinc-sulphate-treated birds, the most notable result being a significant difference in homing success. Taken together, these results highlight the importance of atmospheric odours for the operation of the navigational map of the homing pigeon in a desert environment and, together with previous experiments, demonstrate that the role of atmospheric odours in homing does not seem to vary in any salient way with ambient climatic conditions.

Journal Article↗

PubMed2002

Smelling home: a good solution for burrow-finding in nocturnal petrels?

Many burrowing petrels are able to return to their nests in complete darkness. The well-developed anatomy of their olfactory system and the attraction that food-related odour cues have for some petrel species suggest that olfaction may be used to recognize the burrow. In contrast, surface-nesting petrels may rely on visual cues to recognise their nest. We performed experiments on nine species of petrel (with different nesting habits) rendered anosmic either by plugging the nostrils or by injecting zinc sulphate onto the nasal epithelium. Compared with shamtreated control birds, we found that anosmia impaired nest recognition only in species that nest in burrows and that return home in darkness. Therefore, petrels showing nocturnal activity on land may rely on their sense of smell to find their burrows, while petrels showing diurnal activity or surface nesters may disregard olfactory cues in favour of visual guidance.

Animals↗

PubMed2004

Bilateral choanal atresia in an adult: is it compatible with life?

Bilateral choanal atresia is potentially life-threatening. The condition almost always presents in the new born, with alternating phases of respiratory distress and apnoea relieved by crying. We report a rare case of bilateral choanal atresia presenting for the first time at 22 years of age. The patient had no features of cyanosis or apnoea, presenting only with bilateral nasal obstruction, rhinorrhoea and anosmia. His neonatal history was unremarkable. No syndromic association was noted excepting for telecanthus. The presence of bony atresia was confirmed on computed tomography (CT) scan and transnasal endoscopic surgery was used to obtain a patent airway. This case is a rare report of bilateral choanal atresia presenting for the first time in adult life.

Adult↗

PubMed1984

Transsphenoidal approach to the sella: the Johns Hopkins experience.

The transsphenoidal hypophysectomy has become a relatively frequent procedure in recent years, with the otolaryngologist playing a major role in its renewed popularity. This paper reviews the evolution of pituitary surgery, discusses the surgical technique currently used, and reviews the results and complications of 114 cases over a 13-year period. Of the 129 procedures performed at Johns Hopkins Hospital between 1970 and 1983, 114 charts were available for review. Twelve of these were palliative hypophysectomies and 102 were for sella tumors. Sixty-eight patients were treated with surgery alone, and 34 received surgery and postoperative irradiation. Significant complications such as CSF rhinorrhea, diabetes insipidus, meningitis, septal perforation, anosmia, and visual field defects are discussed. The mortality rate for the series was 1.7%. These results are compared with those of previously published series and the differences are discussed in detail. In analyzing these data we feel that the transseptal, transsphenoidal hypophysectomy has become a safe and effective therapy for sella lesions.

History, 20th Century↗

PubMed1995

Chronic sinusitis.

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Chronic Disease↗

PubMed1977

Outbreak of chronic arsenic poisoning among retired workers from an arsenic mine in Japan.

Retired former workers of Matsuo Arsenic Mine of Miyazaki prefecture in Japan were subjected to extensive medical examination. The number of retired workers subjected to examination were 61 of 208 workers who were engaged in the works of the mine and were tracked down by the work rolls. These workers left the mine more than 15 years prior to the time of the examination. The main works in the mine were classified as mining, dressing of ores, refining, and clerical work. Several findings such as arsenodermatitis, depigmentation, performation of nasal septum, hyposmia, anosmia, and peripheral nervous disturbance attributed to exposure to arsenic were observed in 9 of 21 roasters who often worked in the arsenic kitchen. No characteristic findings of arsenic poisoning, that is, gastrointestinal disturbance, disorder of the cardiovascular system, hematopoietic disorders, or liver disturbance were observed in the retired workers. Another notable finding was that 8 cases diagnosed as pneumoconiosis were found in 18 miners.

Adult↗

PubMed2006

Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.

Chromosome Segregation↗

PubMed2003

Natural history and clinical features of aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis, nasal polyposis, asthma and precipitation of asthma, and rhinitis attacks after ingestion of aspirin (ASA) and most other nonsteroidal antiinflammatory drugs (NSAIDs). Although precipitation of asthma attacks by ingestion of ASA and other NSAIDs is considered a hallmark of the syndrome, the respiratory mucosal inflammatory disease process begins and continues in the absence of ongoing or even intermittent exposure to ASA or NSAIDs. The typical patient with AERD is an adult who develops refractory chronic rhinitis in the third or fourth decade of life. The chronic rhinitis evolves into chronic eosinophilic rhinosinusitis with associated nasal polyposis. Anosmia appears in most patients. CT of the sinuses most often demonstrates pansinusitis and patients often undergo multiple sinus operations resulting in only limited temporary benefit. During the evolution of the sinus disease persistent asthma develops. Finally, if patients are exposed to ASA or NSAIDs acute respiratory reactions begin to occur. Despite subsequent avoidance of ASA and other NSAIDs, the respiratory mucosal inflammatory disease persists, often requiring systemic corticosteroids for control of both upper- and lower-respiratory tract symptoms. Adequate control of asthma can often only be accomplished with the simultaneous control of the associated rhinosinusitis. With few exceptions, once AERD develops it remains for the remainder of the patient s life.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1991

[A case of two successful deliveries by a woman with Kallmann syndrome and NIDDM].

A 37 year-old female with Kallmann syndrome and NIDDM who had two successful deliveries is reported. She had experienced no menstruation until she had treatment with gestagen in her early twenties. She had withdrawal bleeding only once. At the age of 25, she consulted her family doctor, complaining of amenorrhea. Estrogen progesterone cyclic therapy caused withdrawal bleeding, and clomiphene citrate failed to induce apparent ovulation. In January 1978, 150 IU of hMG was administered daily for 9 days, and then 3000 IU of hCG daily for the following 2 days. This therapy induced pregnancy, which failed spontaneously on June 4th. A year later, in January 1979, 150 IU of hMG was again administered daily for 7 days followed by 6000 IU of hCG for 3 days. This therapy again induced pregnancy. On September 27th, 1979, she delivered a girl vaginally, weighing 3830 g. After this delivery, she experienced no menstruation. In June 1985, she consulted her family doctor again, and she was diagnosed as being pregnant. Since her fasting blood glucose was 145 mg/dl, she was admitted to Kosei Hospital to control her blood glucose. On October 15th, she delivered a girl weighing 2600 g. On June 13th, 1989, she was referred to Kosei Hospital by her family doctor to achieve an accurate control of her blood glucose. During this admission, she was diagnosed as having Kallmann syndrome because of congenital anosmia and hypogonadotropic hypogonadism without any abnormal morphological changes. Vitamin B1 infusion test was negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗