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Summary Objective Adult subjects with isolated growth hormone deficiency (IGHD) due to a mutation in the growth hormone releasing hormone receptor gene exhibit higher values formant frequencies. In normal subjects, a significant negative association between the formant frequencies and the reduction of linear craniofacial measurements, especially of maxilla and mandible, has been reported. This suggests smaller pharyngeal width, despite low prevalence of obstructive sleep apnea syndrome. Here we evaluate their pharyngeal airway width, its correlation with vowel formant frequencies, and the correlation between them and the craniofacial measures. Subjects and Methods A two-step protocol was performed. In the first case-control experiment, aimed to assess the pharyngeal width, we compared nine adult IGHD and 36 normal statured controls. Both upper and lower pharyngeal widths were measured. The second step (assessment of pharyngeal width) was performed only in the IGHD group. Results Upper and lower pharyngeal widths were similar in IGHD and controls. In IGHD subjects, the lower pharyngeal width exhibited a negative correlation with F1 [a] and a positive correlation with mandibular length. There were negative correlations between F1 and F2 with linear and positive correlations with the angular measures. Conclusions Pharyngeal airway width is not reduced in adults with congenital, untreated lifetime IGHD, contributing to the low prevalence of obstructive sleep apnea syndrome. The formant frequencies relate more with cephalometric measurements than with the pharyngeal airway width. These findings exemplify the consequences of lifetime IGHD on osseous and nonosseous growth.

Body balance involves the vestibular, visual, and proprioceptive systems. IGF-I is a GH-dependent key factor in the development and postnatal differentiation of the inner ear in mice and men, but its role in the vestibular function in adult humans is unknown. We have previously described a cohort of individuals with severe isolated GH deficiency (IGHD) caused by a mutation in the GHRH receptor (GHRHR) gene. These individuals complain of dizziness, exhibit mild sensorineural loss, but have normal postural balance, without increase in falls risk. The aim of this study was to evaluate their vestibular function. We performed physical examination (clinical head impulse and Fukuda dynamic stepping test), oculomotor (saccadic eye movements, spontaneous, semi-spontaneous and opotokinetic nystagmus, and pendular tracking) and caloric stimulation (postcaloric reflex and ocular fixation index) tests, in 15 GH-naive IGHD (seven males) and 15 controls (five males). IGHD subjects showed lower height and weight, with similar BMI to controls, and higher number of individuals with abnormal clinical head impulse test and abnormal oculomotor tests, namely the saccadic movements and the spontaneous nystagmus. There was a nonsignificant trend in abnormalities in the Fukuda stepping test and postcaloric reflex test. Adult untreated IGHD individuals have higher prevalence of moderate peripheral vestibular impairment, and of abnormal vestibular-ocular reflex.

Body balance involves the vestibular, visual, and proprioceptive systems. IGF-I is a GH-dependent key factor in the development and postnatal differentiation of the inner ear in mice and men, but its role in the vestibular function in adult humans is unknown. We have previously described a cohort of individuals with severe isolated GH deficiency (IGHD) caused by a mutation in the GHRH receptor (GHRHR) gene. These individuals complain of dizziness, exhibit mild sensorineural loss, but have normal postural balance, without increase in falls risk. The aim of this study was to evaluate their vestibular function.We performed physical examination (clinical head impulse and Fukuda dynamic stepping test), oculomotor (saccadic eye movements, spontaneous, semi-spontaneous and opotokinetic nystagmus, and pendular tracking) and caloric stimulation (postcaloric reflex and ocular fixation index) tests, in 15 GH-naïve IGHD (seven males) and 15 controls (five males).IGHD subjects showed lower height and weight, with similar BMI to controls, and higher number of individuals with abnormal clinical head impulse test and abnormal oculomotor tests, namely the saccadic movements and the spontaneous nystagmus. There was a nonsignificant trend in abnormalities in the Fukuda stepping test and postcaloric reflex test.Adult untreated IGHD individuals have higher prevalence of moderate peripheral vestibular impairment, and of abnormal vestibular-ocular reflex.

Summary Objective To analyze the voice formants (F1, F2, F3, and F4 in Hz) of seven oral vowels, in Brazilian Portuguese, [a, e, e, i, ɔ, o, and u] in adult individuals with congenital lifetime untreated isolated growth hormone deficiency (IGHD). Study Design This is a cross-sectional study. Methods Acoustic analysis of isolated vowels was performed in 33 individuals with IGHD, age 44.5 (17.6) years (16 women), and 29 controls, age 51.1 (17.6) years (15 women). Results Compared with controls, IGHD men showed higher values of F3 [i, e, and e], P = 0.006, P = 0.022, and P = 0.006, respectively and F4 [i], P = 0.001 and lower values of F2 [u], P = 0.034; IGHD women presented higher values of F1 [i and e] P = 0.029 and P = 0.036; F2 [ɔ] P = 0.006; F4 [ɔ] P = 0.031 and lower values of F2 [i] P = 0.004. IGHD abolished most of the gender differences in formant frequencies present in controls. Conclusions Congenital, severe IGHD results in higher values of most formant frequencies, suggesting smaller oral and pharyngeal cavities. In addition, it causes a reduction in the effect of gender on the structure of the formants, maintaining a prepubertal acoustic prediction.

The GH/IGF-I axis has important interactions with the alimentary system and with the balance between energy intake (EI) and energy requirement (ER). Reduced EI has been described in adult-onset acquired GH deficiency (GHD). Individuals from the Brazilian Itabaianinha cohort, with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G→A) in the GHRH receptor gene, are an ideal model to study the consequences of lifetime GHD. The purpose of this study is to evaluate EI and ER in this untreated IGHD cohort. Cross-sectional study of 24 adult IGHD patients and 23 controls from the same region, matched for age and gender. Estimated EI (EEI) was evaluated by dietary recall, and estimated ER (EER) by the equation of the Dietary Reference Intakes. Fat mass was assessed by DXA. Both EEI and EER were lower in IGHD than controls. However, when corrected by body weight, EEI was higher in IGHD (p = 0.005). IGHD individuals consume in percentage more proteins (p < 0.0001), less carbohydrates (p = 0.013), and equal amount of lipids in comparison to controls. The higher EEI per body weight suggests a possible increase of orexigenic mechanisms in untreated IGHD individuals, ensuring greater caloric intake, which would have adaptive advantages for small-sized individuals in environments with limited access to food. IGHD individuals seem to have a healthier dietary pattern than CO.

Growth hormone (GH)-releasing hormone (GHRH) is the most important stimulus for GH secretion by the pituitary gland. Subjects homozygous for GHRH receptor (GHRHR) gene (GHRHR) inactivating mutations have severe GH deficiency, resulting in severe short stature if not treated. We previously reported that young adults heterozygous for the c.57+1GA null GHRHR mutation (MUT/N) have reduced weight and body mass index (BMI) but normal stature. Here we have studied whether older MUT/N have an additional phenotype. In a cross-sectional study, we measured height, weight and blood pressure, and calculated BMI in two groups (young, 20-40 years of age) and old (60-80 years) of individuals heterozygous for the same GHRHR mutation, and compared with a large number of individuals of normal genotype residing in the same geographical area. Standard deviation score (SDS) of weight was lower, and BMI had a trend toward reduction in young heterozygous compared with young normals, without significant difference in stature. Conversely, SDS of height was lower in older heterozygous individuals than in controls, corresponding to a reduction of 4.2 cm. These data show a reduced stature in older subjects heterozygous for the c.57+1GA GHRHR mutation, indicating different effects of heterozygosis through lifespan.

Nonalcoholic fatty liver disease (NAFLD) is known to be associated with insulin resistance, atherosclerosis, and low serum IGF1 levels. We have described a large cohort of patients with isolated GH deficiency (IGHD) due to the c.57+1G→A mutation in the GHRH receptor gene. These subjects have increased insulin sensitivity (IS), delayed atherosclerosis, and normal longevity. We hypothesized that, despite visceral obesity, NAFLD would be absent or mild due to the increased IS. To assess the prevalence and severity of NAFLD in adult subjects with lifetime, congenital, untreated IGHD, we studied 22 IGHD adults and 25 controls (COs) matched for age and sex. NAFLD was assessed by a comprehensive liver function panel, and ultrasonographic pattern (hyperechogenic pattern, HP) coded as follows: 0, absent; 1, mild; 2, moderate; and 3, severe. Compared with COs, IGHD individual had lower serum IGF1 (PP=0.027), lower prothrombin time (P=0.017), and similar activated partial thromboplastin time and fibrinogen values. Alanine transaminase (ALT) values were similar in the two groups, but aspartate transaminase was higher in IGHD (P=0.013). However, more IGHD subjects (7/22) than COs (3/23) had ALT above the upper limit of normal (P=0.044). The prevalence of NAFLD was higher in IGHD than COs (61 vs 29%, P=0.032), and the HP score was higher in IGHD than COs (P=0.041), but severe NAFLD was not observed in any IGHD (or CO) individual. Liver HP score is increased in lifetime, untreated, congenital IGHD, but the increase in transaminases is mild, suggesting a lack of advanced forms of NAFLD.

Summary Objectives Voice is produced by the vibration of the vocal folds expressed by its fundamental frequency (Hz), whereas the formants (F) are fundamental frequency multiples, indicating amplification zones of the vowels in the vocal tract. We have shown that lifetime isolated growth hormone deficiency (IGHD) causes high pitch voice, with higher values of most formant frequencies, maintaining a prepuberal acoustic prediction. The objectives of this work were to verify the effects of the therapy with a semi-occluded vocal tract (SOVTT) and choir training on voice in these subjects with IGHD. We speculated that acoustic vocal parameters can be improved by SOVTT or choir training. Study Design This is a prospective longitudinal study without control group. Methods Acoustic analysis of isolated vowels was performed in 17 adults with IGHD before and after SOVTT (pre-SOVTT and post-SOVTT) and after choir training (post training), in a 30-day period. Results The first formant was higher in post training compared with the pre-SOVTT (P = 0.009). The second formant was higher in post-SOVTT than in pre-SOVTT (P = 0.045). There was a trend of reduction in shimmer in post-choir training in comparison with pre-SOVTT (P = 0.051), and a reduction in post-choir training in comparison with post-SOVTT (P = 0.047). Conclusions SOVTT was relevant to the second formant, whereas choir training improved first formant and shimmer. Therefore, this speech therapy approach was able to improve acoustic parameters of the voice of individuals with congenital, untreated IGHD. This seems particularly important in a scenario in which few patients are submitted to growth hormone replacement therapy.

To evaluate the hearing status of growth hormone (GH)-naive adults with isolated GH deficiency (IGHD) belonging to an extended Brazilian kindred with a homozygous mutation in the GH-releasing hormone receptor gene.Cross-sectional.Divisions of Endocrinology and Otorhinolaryngology of the Federal University of Sergipe.Twenty-six individuals with IGHD (age, 47.6 ± 15.1 years; 13 women) and 25 controls (age, 46.3 ± 14.3 years; 15 women) were administered a questionnaire on hearing complaints and hearing health history. We performed pure-tone audiometry, logoaudiometry, electroacoustic immittance, and stapedial reflex. To assess outer hair cell function in the cochlea, we completed transient evoked otoacoustic emissions (TEOAEs). To assess the auditory nerve and auditory brainstem, we obtained auditory brainstem responses (ABRs).Misophonia and dizziness complaints were more frequent in those with IGHD than in controls (P = .011). Patients with IGHD had higher thresholds at 250 Hz (P = .005), 500 Hz (P = .006), 3 KHz (P = .008), 4 KHz (P = .038), 6 KHz (P = .008), and 8 KHz (P = .048) and mild high-tones hearing loss (P = .029). Stapedial reflex (P.001) and TEOAEs (P = .025) were more frequent in controls. There were no differences in ABR latencies. Hearing loss in patients with IGHD occurred earlier than in controls (P.001).Compared with controls of the same area, subjects with untreated, congenital lifetime IGHD report more misophonia and dizziness, have predominance of mild high-tones sensorineural hearing loss, and have an absence of stapedial reflex and TEOAEs.

Objective Ocular function is fundamental for environmental adaptation and survival capacity. Growth factors are necessary for a mature eyeball, needed for adequate vision. However, the consequences of the deficiency of circulating growth hormone (GH) and its effector insulin-like growth factor I (IGF-I) on the physical aspects of the human eye are still debated. A model of untreated isolated GH deficiency (IGHD), with low but measurable serum GH, may clarify this issue. The aim of this study was to assess the ocular aspects of adult IGHD individuals who have never received GH therapy. Design Cross sectional study. Methods Setting : University Hospital, Federal University of Sergipe, Brazil. Patients : Twenty-five adult (13 males, mean age 50.1years, range 26 to 70years old) IGHD subjects homozygous for a null mutation (c.57+1G>A) in the GHRH receptor gene, and 28 (15 males, mean age 51.1years, range 26 to 67years old) controls were submitted to an endocrine and ophthalmological assessment. Forty-six IGHD and 50 control eyes were studied. Main outcome measures : Visual acuity, intraocular pressure, refraction (spherical equivalent), ocular axial length (AL), anterior chamber depth (ACD), lens thickness (LT), vitreous depth (VD), mean corneal curvature (CC) and central corneal thickness (CCT). Results IGHD subjects exhibited unmeasurable serum IGF-I levels, similar visual acuity, intraocular pressure and LT, higher values of spherical equivalent and CC, and lower measures of AL, ACD, VD and CCT in comparison to controls, but within their respective normal ranges. While mean stature in IGHD group was 78% of the control group, mean head circumference was 92% and axial AL was 96%. Conclusions These observations suggest mild ocular effects in adult subjects with severe IGF-I deficiency due to non-treated IGHD.

OBJECTIVE: To analyze cephalometric features in adults with isolated growth hormone (GH) deficiency (IGHD). MATERIALS AND METHODS: Nine adult IGHD individuals (7 males and 2 females; mean age, 37.8 ± 13.8 years) underwent a cross-sectional cephalometric study, including 9 linear and 5 angular measurements. Posterior facial height/anterior facial height and lower-anterior facial height/anterior facial height ratios were calculated. To pool cephalometric measurements in both genders, results were normalized by standard deviation scores (SDS), using the population means from an atlas of the normal Brazilian population. RESULTS: All linear measurements were reduced in IGHD subjects. Total maxillary length was the most reduced parameter (−6.5 ± 1.7), followed by a cluster of six measurements: posterior cranial base length (−4.9 ± 1.1), total mandibular length (−4.4 ± 0.7), total posterior facial height (−4.4 ± 1.1), total anterior facial height (−4.3 ± 0.9), mandibular corpus length (−4.2 ± 0.8), and anterior cranial base length (−4.1 ± 1.7). Less affected measurements were lower-anterior facial height (−2.7 ± 0.7) and mandibular ramus height (−2.5 ± 1.5). SDS angular measurements were in the normal range, except for increased gonial angle (+2.5 ± 1.1). Posterior facial height/anterior facial height and lower-anterior facial height/anterior facial height ratios were not different from those of the reference group. CONCLUSIONS: Congenital, untreated IGHD causes reduction of all linear measurements of craniofacial growth, particularly total maxillary length. Angular measurements and facial height ratios are less affected, suggesting that lGHD causes proportional blunting of craniofacial growth.

The GH/IGF-I axis has essential roles in regulating bone and vascular status. The age-related decrease in GH secretion ("somatopause") may contribute to osteoporosis and atherosclerosis, commonly observed in the elderly. Adult-onset GH deficiency (GHD) has been reported to be associated with reduced bone mineral density (BMD), increased risk of fractures, and premature atherosclerosis. We have shown the young adult individuals with isolated GHD (IGHD) due to a homozygous for the c.57+1G>A GHRH receptor gene mutation have normal volumetric BMD (vBMD), and not develop premature atherosclerosis, despite adverse risk factor profile. However, the bone and vascular impact of lifetime GHD on the aging process remains unknown. We studied a group of ten older IGHD subjects (≥60 years) homozygous for the mutation, comparing them with 20 age- and gender-matched controls (CO). Areal BMD was measured, and vBMD was calculated at the lumbar spine and total hip. Vertebral fractures and abdominal aortic calcifications (expressed as calcium score) were also assessed. Areal BMD was lower in IGHD, but vBMD was similar in the two groups. The percent of fractured individuals was similar, but the mean number of fractures per individual was lower in IGHD than CO. Calcium score was similar in the two groups. A positive correlation was found between calcium score and number of fractures. Untreated lifetime IGHD has beneficial consequences on bone status and does not have a deleterious effect on abdominal aorta calcification.

ObjectivesAdult subjects with untreated, lifetime, isolated GH deficiency (IGHD) due to a homozygous GHRH receptor gene mutation (MUT/MUT) residing in Itabaianinha, Brazil, present with lower BMI, higher prevalence of impaired glucose tolerance (IGT), increased insulin sensitivity (IS), and reduced β-cell function (βCF) when compared with non-BMI-matched homozygous normal controls. However, the prevalence of diabetes mellitus (DM) in this cohort is unknown. Comparing their IS and βCF with BMI-matched individuals heterozygous for the same mutation (MUT/N) may be useful to elucidate the role of the GH–IGF1 axis in IS and βCF. The purposes of this work were to verify the prevalence of IGT and DM in adult MUT/MUT subjects from this kindred and to compare IS and βCF in MUT/MUT and MUT/N.DesignCross-sectional study.MethodsWe studied most (51) of the living IGHD adults of this kindred who are GH naive. The oral glucose tolerance test (OGTT) could be performed in 34 subjects, fasting glucose was measured in 15, while two had a previous diagnosis of DM. The OGTT results of 24 MUT/MUT subjects were compared with those of 25 BMI-matched MUT/N subjects. IS was assessed by homeostatic model assessment of insulin resistance (HOMA–IR), quantitative IS check index, and oral glucose IS index for 2 and 3 h. βCF was assayed by HOMA-β, insulinogenic index, and the area under the curve of insulin:glucose ratio.ResultsThe prevalence of DM and IGT in IGHD was 15.68 and 38.23% respectively. IS was increased and βCF was reduced in MUT/MUT in comparison with MUT/N.ConclusionsLifetime, untreated IGHD increases IS, impairs βCF, and does not provide protection from diabetes.

The GH/IGF-I axis is important for bone growth, but its effects on joint function are not completely understood. Adult-onset GH-deficient individuals have often reduced bone mineral density (BMD). However, there are limited data on BMD in adult patients with untreated congenital isolated GH-deficient (IGHD). We have shown that adult IGHD individuals from the Itabaianinha, homozygous for the c.57+1GA GHRHR mutation, have reduced bone stiffness, but BMD and joint status in this cohort are unknown.The goal is to study BMD, joint function, and osteoarthritis score in previously untreated IGHD adults harboring the c.57+1GA GHRHR mutation.This is a cross-sectional study.Areal BMD by dual-energy X-ray absorptiometry was measured in 25 IGHD and 23 controls (CO). Volumetric BMD (vBMD) was calculated at the lumbar spine and total hip. Joint function was assessed by goniometry of elbow, hips, and knees. X-rays were used to measure the anatomic axis of knee and the severity of osteoarthritis, using a classification for osteophytes (OP) and joint space narrowing (JSN).Genu valgum was more prevalent in IGHD than CO. The osteoarthritis knees OP score was similar in both groups, and knees JSN score showed a trend to be higher in IGHD. The hips OP score and JSN score were higher in IGHD. Areal BMD was lower in IGHD than CO, but vBMD was similar in the two groups. Range of motion was similar in elbow, knee, and hip in IGHD and CO.Untreated congenital IGHD due to a GHRHR mutation causes hip joint problems and genu valgum, without apparent clinical significance, reduces bone size, but does not reduce vBMD of the lumbar spine and hip.

Growth hormone (GH) and prolactin share similarities in structure and function. We have previously shown that women with congenital isolated GH deficiency (IGHD) caused by a homozygous mutation in the GHRH receptor gene (GHRHR) (MUT/MUT) have a short reproductive life, with anticipated climacteric. At climacteric, they have lower prolactin levels than normal controls (N/N). Because they are able to breast feed, we hypothesized that this prolactin reduction is limited to climacteric, as result of lower estradiol exposure of the lactotrophs. The purposes of this work were to assess prolactin levels in broader age adults homozygous and heterozygous (MUT/N) for the mutation and in normal controls (N/N), and to correlate them to sex steroids levels. We enrolled 24 GH-naive MUT/MUT (12 female), 25 MUT/N (14 female), and 25 N/N (11 female) subjects, aged 25-65 years. Anthropometric data and serum prolactin, estradiol, total testosterone, and sex hormone binding globulin (SHBG) were measured. Free testosterone was calculated. Prolactin levels were similar in the three groups. In males, testosterone and SHBG levels were higher in MUT/MUT in comparison to N/N. There was no difference in free testosterone among groups. In all 74 individuals, prolactin correlated inversely with age (p < 0.0001) and directly with serum estradiol (p = 0.018). Prolactin levels in subjects with IGHD due to a homozygous GHRHR mutation are similar to heterozygous and normal homozygous, but total testosterone and SHBG are higher in male MUT/MUT, with no difference in free testosterone. The reduced prolactin level is limited to climacteric period, possibly due to reduced estrogen exposure.

ObjectiveGH replacement therapy (GHRT) in adult-onset GH deficiency (AOGHD) reduces carotid intima-media thickness (IMT) and increases myocardial mass, with improvement of systolic and diastolic function. These observations have reinforced the use of GHRT on AOGHD. Conversely, we have previously reported that in adults with lifetime congenital and severe isolated GH deficiency (IGHD) due to a mutation in GHRH receptor gene (GHRHR), a 6-month treatment with depot GH increased carotid IMT, caused the development of atherosclerotic plaques, and an increase in left ventricular mass index (LVMI), posterior wall, and septal thickness and ejection fraction. Such effects persisted 12 months after treatment (12-month washout – 12mo).MethodsWe have studied the cardiovascular status (by echocardiography and carotid ultrasonography) of these subjects 60 months after completion of therapy (60-month washout – 60mo).ResultsCarotid IMT reduced significantly from 12 to 60mo, returning to baseline (pre-therapy) value. The number of individuals with plaques was similar at 12 and 60mo, remaining higher than pre-therapy. LVMI, relative posterior wall thickness, and septum thickness did not change between 12 and 60mo, but absolute posterior wall increased from 12 to 60mo. Systolic function, evaluated by ejection fraction and shortening fraction, was reduced at 60mo in comparison with 12mo returning to baseline levels. The E/A wave ratio (expression of diastolic function) decreased at 60mo compared with both 12mo and baseline.ConclusionsIn adults with lifetime congenital IGHD, the increase in carotid IMT elicited by GHRT was transitory and returned to baseline 5 years after therapy discontinuation. Despite this, the number of subjects with plaques remained stable at 60mo and higher than at baseline.

The aim of this study was to analyze the individual impact of short stature (SS) or untreated isolated growth hormone deficiency (IGHD) on voice quality and the influence of IGHD on voice aging.A cross-sectional study was carried out on 73 adults: 33 IGHD, 10 SS, and 30 normal controls (CO), by evaluating vocal perception using Voice-Related Quality-of-Life (V-RQOL) scores and fundamental frequency (ƒ0). Analysis of variance with Bonferroni post-test was used to compare groups, and the Student t test was used to verify the influence of aging.Stature of the SS and IGHD groups was similarly reduced in comparison to CO. Cephalic perimeter (CP) in SS males was larger than CO (P0.05), and this was larger than in IGHD (P0.0001). CP was similar in SS and CO females, and both were larger than in IGHD (P0.0001). V-RQOL scores were lower in IGHD than in SS and CO. ƒ0 (Hz) was similar in IGHD females and SS and higher than in CO (P0.05). f0 of IGHD males was higher than in SS (P=0.01) and CO (P=0.001). IGHD abolished the effect of aging on ƒ0 exhibited by CO.Lower vocal perception and higher ƒ0 were found in IGHD in comparison to CO in both genders; in comparison to SS, higher ƒ0 was only found in IGHD males. Because SS males have higher CP than IGHD, this suggests that CP and craniofacial growth can influence voice in IGHD. Finally, IGHD seems to abolish the effects of aging on voice.

Context: Reduced longevity observed in hypopituitarism has been attributed to GH deficiency (GHD). It is, however, unclear whether GHD or other confounding factors cause this early mortality. Objective: The aim was to study longevity in subjects from a large kindred with untreated, lifetime isolated GHD (IGHD) due to a homozygous mutation in the GHRH receptor gene and in heterozygous carriers of the mutation. Design, Setting, and Participants: We carried out a retrospective cohort study on three groups. We first compared mortality risk of 65 IGHD individuals and their 128 unaffected siblings from 34 families. We then compared mean age of death of the IGHD to the general population. A transversal study was carried out to compare the rate of heterozygosity for the mutation in two groups of young (20–40 yr old) and old (60–80 yr old) normal-appearing subjects from the same county. Main Outcome Measure: We measured longevity. Results: The risk of death of IGHD subjects was not different from their siblings. Life span in IGHD individuals was shorter than the general population. When stratified by sex, this difference persisted only in females, due to a high frequency of IGHD deaths in females aged 4–20. There was no significant difference in life span between IGHD subjects and siblings or the general population when analyzing subjects who reached age 20. The prevalence of heterozygosity did not differ in young and old groups, suggesting no survival advantage or disadvantage. Conclusions: In a selected genetic background, lifelong untreated IGHD does not affect longevity.