Scientific letter
Late-diagnosed Kallmann syndrome
Síndrome de Kallmann de diagnóstico tardío
M. del Carmen Cabrejas Gómez
, M. Ángeles Vicente Vicente, M. Ángeles Antón Miguel, Miren Urcelay Rojo
Corresponding author
Servicio de Endocrinología y Nutrición, Hospital Universitario de Álava, Sede de Txagorritxu, Vitoria, Álava, Spain
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Ángeles Vicente Vicente, M. Ángeles Antón Miguel, Miren Urcelay Rojo" "autores" => array:4 [ 0 => array:4 [ "nombre" => "M. del Carmen" "apellidos" => "Cabrejas Gómez" "email" => array:1 [ 0 => "carmenmallen2000@yahoo.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "M. Ángeles" "apellidos" => "Vicente Vicente" ] 2 => array:2 [ "nombre" => "M. Ángeles" "apellidos" => "Antón Miguel" ] 3 => array:2 [ "nombre" => "Miren" "apellidos" => "Urcelay Rojo" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Endocrinología y Nutrición, Hospital Universitario de Álava, Sede de Txagorritxu, Vitoria, Álava, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de Kallmann de diagnóstico tardío" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Kallmann syndrome is the most common form of isolated hypogonadotropic hypogonadism with delayed puberty. The syndrome characteristically includes GnRH deficiency associated with anosmia or hyposmia due to agenesis or hypoplasia of the olfactory bulbs.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> This is a hereditary, genetically heterogeneous disease that may be transmitted as an <span class="elsevierStyleSmallCaps">X</span> chromosome-linked trait or as an autosomal dominant or recessive trait. Its incidence is approximately 1/8000 in males and 1/40,000 in females.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a> It is usually diagnosed at 14–16 years of age when medical advice is sought for delayed puberty.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The first case reported was a 52-year-old male who was referred for severe osteoporosis with hypogonadal phenotype. His clinical history included severe hearing loss in the left ear and a cleft lip from birth. Examination revealed an absence of body hair, cryptorchidism, micropenis, and gynecomasty. The patient had previously concealed these signs. Hypogonadism was suspected based on the clinical data, and hormone and imaging tests were performed. Hormone test results (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) suggested hypogonadotropic hypogonadism. Brain MRI confirmed severe hypoplasia of both olfactory bulbs. Based on the above data, the most likely diagnosis was Kallmann syndrome.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The second case was a 44-year-old female treated with oral contraceptives since the age of 18 for primary amenorrhea, which persisted after several attempts at treatment discontinuation. In the clinical history, the patient reported anosmia. Hormone tests revealed hypogonadotropic hypogonadism, a densitometric study showed osteoporosis, and brain MRI confirmed severe hypoplasia of both olfactory bulbs.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Kallmann syndrome was first described in 1856.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> The prevalence of the syndrome is approximately four times greater in males as compared to females. From the pathophysiological viewpoint, it is explained by a defect in the migration of GnRH-secreting fetal neurons from the olfactory placode (where they originate) to the medial basal hypothalamus, where they represent the GnRH pulse generator. This defect may be absolute or partial. Because of this, cells that contain GnRH and neurites end up in a tangle around the lamina cribrosa and in the dural layers adjacent to the meninges, below the prosencephalon.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">There are several genes involved in the development of the syndrome. The best known is the KAL1 gene, located in <span class="elsevierStyleItalic">locus</span> Xp 22.3, an X chromosome-linked gene<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> that escapes <span class="elsevierStyleSmallCaps">X</span> inactivation, which is responsible for so-called Kallmann syndrome 1 (KAL1). The KAL1 gene encodes for a 680-amino acid glycoprotein called anosmin-1, with characteristics of extracellular neural adhesion, which may function as an “explorer” to guide GnRH neurons to the medial basal hypothalamus. Anosmin-1 has been shown to be distributed in the olfactory placode and prosencephalon by weeks 5–6 of fetal life. KAL1 gene deletion and/or mutations cause a frameshift and premature stop codons that result in the changes defining Kallmann syndrome.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> This change rarely has an impact on females.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Other hereditary forms are less well known. The autosomal dominant form is known as Kallmann syndrome 2 (KAL2), and the autosomal recessive form is called Kallmann syndrome 3 (KAL3).</p><p id="par0035" class="elsevierStylePara elsevierViewall">The involvement of several genes<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> may account for phenotype variability in each case. However, intrafamilial heterogeneity is also seen.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The cases reported here showed the main two clinical characteristics, hypogonadism and anosmia.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> A detailed clinical history with a special focus on anosmia suggested the diagnosis. It should not be forgotten, however, that there may be other associated characteristics such as gynecomastia, cryptorchidism, micropenis, cleft lip, cleft palate, imperfect facial fusion, seizures, short metacarpal bones, pes cavus, sensorineural hearing loss, cerebellar ataxia, etc., some of which were found in the first patient.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In patients with hyposmia, smell tests are often difficult to interpret. Coronal and axial cranial MRI of olfactory sulci-bulbs provides greater sensitivity, showing olfactory bulb aplasia or hypoplasia in approximately 90% of cases and leading to diagnosis, especially in small and prepubertal children. With MRI, olfactory sulci may be detected from week 30 of pregnancy, and olfactory bulbs between weeks 30 and 34.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> Genetic study is very important, and could almost be considered as mandatory, but was not performed in the reported cases due to patient refusal.</p><p id="par0050" class="elsevierStylePara elsevierViewall">According to the literature, most cases are usually diagnosed at 14–16 years of age.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">8,9</span></a> The uniqueness of our cases lies in their being diagnosed at such a late age. In the first case, late diagnosis was due to a psychosocial and cultural component which had previously prevented the patient from consulting a specialist. By contrast, our second patient consulted a doctor at 18 years of age, but the etiology of primary amenorrhea was not investigated at the time, and was simply treated as a symptom.</p><p id="par0055" class="elsevierStylePara elsevierViewall">When hypogonadism is diagnosed late, its manifestations include absent or poor sexual development inappropriate for the patient's age, eunuchoid proportions due to the late closure of growth cartilages in limbs with a reduced relationship between the upper and lower segment and increased arm span, osteopenia/osteoporosis due to decreased bone matrix mineralization and increased bone resorption, and body composition changes with increased fat mass (including abdominal mass) of gynoid distribution and decreased muscle mass. Late treatment of hypogonadism thus leads to an increase in fracture and cardiovascular risks, and also to earlier aging.</p><p id="par0060" class="elsevierStylePara elsevierViewall">It may be concluded that Kallmann syndrome is an uncommon condition that should be suspected in patients with hypogonadotropic hypogonadism irrespective of age, and that special attention should be paid in the clinical history to the presence of hyposmia.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> This will allow for an adequate diagnosis to be made and, consequently, for early replacement therapy to be started, so decreasing all potential consequences of the deficiency.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Cabrejas Gómez MC, Vicente Vicente MÁ, Antón Miguel MÁ, Urcelay Rojo M. Síndrome de Kallmann de diagnóstico tardío. Endocrinol Nutr. 2015;62:106-108.</p>" ] ] "multimedia" => array:1 [ 0 => array:6 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cortisol (μg/dL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TSH (mU/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Free T4 (ng/dL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FSH (IU/L) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LH (IU/L) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total testosterone (ng/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Free testosterone (pg/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Estradiol (pg/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PRL (ng/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total cholesterol (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HDL (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Triglycerides (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Weight (kg) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">BMI \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Reference values \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6–25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3–4.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9–1.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.9–7.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Case 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.148 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">234 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">106 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22.20 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Case 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">242 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20.42 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab687406.png" ] ] ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.B. 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| Year/Month | Html | Total | |
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| 2024 October | 32 | 6 | 38 |
| 2024 September | 116 | 13 | 129 |
| 2024 August | 91 | 15 | 106 |
| 2024 July | 105 | 14 | 119 |
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| 2024 May | 62 | 9 | 71 |
| 2024 April | 52 | 3 | 55 |
| 2024 March | 109 | 10 | 119 |
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| 2024 January | 90 | 12 | 102 |
| 2023 December | 89 | 13 | 102 |
| 2023 November | 105 | 8 | 113 |
| 2023 October | 129 | 30 | 159 |
| 2023 September | 63 | 2 | 65 |
| 2023 August | 54 | 5 | 59 |
| 2023 July | 98 | 10 | 108 |
| 2023 June | 71 | 17 | 88 |
| 2023 May | 162 | 52 | 214 |
| 2023 April | 96 | 17 | 113 |
| 2023 March | 88 | 6 | 94 |
| 2023 February | 64 | 11 | 75 |
| 2023 January | 91 | 9 | 100 |
| 2022 December | 57 | 12 | 69 |
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| 2022 October | 69 | 20 | 89 |
| 2022 September | 70 | 27 | 97 |
| 2022 August | 101 | 26 | 127 |
| 2022 July | 65 | 13 | 78 |
| 2022 June | 79 | 9 | 88 |
| 2022 May | 88 | 20 | 108 |
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| 2021 February | 105 | 50 | 155 |
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| 2020 December | 106 | 33 | 139 |
| 2020 November | 119 | 40 | 159 |
| 2020 October | 62 | 27 | 89 |
| 2020 September | 73 | 29 | 102 |
| 2020 August | 86 | 21 | 107 |
| 2020 July | 66 | 24 | 90 |
| 2020 June | 64 | 25 | 89 |
| 2020 May | 149 | 32 | 181 |
| 2020 April | 127 | 15 | 142 |
| 2020 March | 113 | 20 | 133 |
| 2020 February | 120 | 19 | 139 |
| 2020 January | 99 | 25 | 124 |
| 2019 December | 87 | 18 | 105 |
| 2019 November | 74 | 24 | 98 |
| 2019 October | 87 | 16 | 103 |
| 2019 September | 71 | 25 | 96 |
| 2019 August | 49 | 12 | 61 |
| 2019 July | 93 | 13 | 106 |
| 2019 June | 121 | 40 | 161 |
| 2019 May | 271 | 61 | 332 |
| 2019 April | 84 | 30 | 114 |
| 2019 March | 40 | 12 | 52 |
| 2019 February | 36 | 14 | 50 |
| 2019 January | 21 | 5 | 26 |
| 2018 December | 29 | 3 | 32 |
| 2018 November | 25 | 2 | 27 |
| 2018 October | 28 | 5 | 33 |
| 2018 September | 45 | 4 | 49 |
| 2018 August | 17 | 2 | 19 |
| 2018 July | 8 | 2 | 10 |
| 2018 June | 8 | 4 | 12 |
| 2018 May | 9 | 0 | 9 |
| 2018 April | 8 | 3 | 11 |
| 2018 March | 4 | 0 | 4 |
| 2018 February | 8 | 6 | 14 |
| 2018 January | 5 | 0 | 5 |
| 2017 December | 9 | 1 | 10 |
| 2017 November | 10 | 2 | 12 |
| 2017 October | 9 | 2 | 11 |
| 2017 September | 6 | 5 | 11 |
| 2017 August | 20 | 2 | 22 |
| 2017 July | 14 | 2 | 16 |
| 2017 June | 36 | 15 | 51 |
| 2017 May | 26 | 6 | 32 |
| 2017 April | 35 | 7 | 42 |
| 2017 March | 30 | 30 | 60 |
| 2017 February | 46 | 5 | 51 |
| 2017 January | 21 | 1 | 22 |
| 2016 December | 23 | 3 | 26 |
| 2016 November | 23 | 3 | 26 |
| 2016 October | 63 | 4 | 67 |
| 2016 September | 25 | 2 | 27 |
| 2016 August | 19 | 4 | 23 |
| 2016 July | 15 | 4 | 19 |
| 2016 June | 20 | 3 | 23 |
| 2016 May | 19 | 8 | 27 |
| 2016 April | 23 | 4 | 27 |
| 2016 March | 19 | 5 | 24 |
| 2016 February | 32 | 6 | 38 |
| 2016 January | 22 | 8 | 30 |
| 2015 December | 30 | 10 | 40 |
| 2015 November | 25 | 8 | 33 |
| 2015 July | 1 | 1 | 2 |
| 2015 April | 0 | 1 | 1 |
| 2015 March | 0 | 1 | 1 |
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