The patient described herein is, to our knowledge, the oldest adult case of IGHDIA properly described in the literature. Genetic analysis revealed a 6.7
kb deletion in GH1
gene that entails an absolute lack of GH. Deletion of 6.7
kb has been reported to be the most common mutation accounting for the type IA phenotype (78%); other deletions include 7.6 and 45
. Less severe mutations in GH1
gene (splice site and missense) exhibit phenotype IB or II, in which low but detectable GH concentrations are observed and there is response to GH replacement. Type IB can also be caused by recessive GHRHR
mutations. Type IA is less frequent than type IB or type II, accounting for only about 5% of the cases (4)
. However, in the work carried out by Wagner et al.
, the absolute frequency of GH1
gene deletions in a cohort of severe short stature (<4.5 s.d
.) was 12.5% (19/151), especially in those of an Asian origin.
Phenotypic appearance of GHDIA includes an already intrauterine growth retardation (birth length <49
cm, considerably shorter than nonaffected siblings) and severe growth delay in childhood, even beyond −4.5 SDS. Adult height is clearly small, but quite variable in the few adult cases reported in the literature (130–140
cm), as some do not produce anti-GH Abs or would not have received rhIGF1 therapy in childhood (6)
. Cherubic facial features derive from midfacial hypoplasia and forehead prominence. Small posterior fossa and platybasia described in our patient's MRI may also reveal bone effects of lifelong GHD. On the other hand, the pituitary arachnoidocele found in the MRI is meant to have developed with time; possibly, it is merely a coincidental finding, but more information about adult IGHDIA cases is lacking. Generally, cases with mutations in GH1
gene have normal pituitary morphology in contrast to cases with other causes of congenital GHD such as perinatal insults that are associated with alterations in the pituitary stalk or ectopic posterior pituitary lobe. However, some cases present with anterior hypoplasia, and it is not ruled out that pituitary image findings may evolve with time. Oliveira et al
reported anterior pituitary hypoplasia in patients with inactivating GHRHR
mutations, compatible with the lack of GHRH effect on somatotrophs. Our patient has not developed any other hormonal deficiency until now. Development of additional pituitary hormone deficiencies in type II IGHD has been attributed to the disrupting effects of the aberrant predominance of 17.5
kDa GH isoform on the pituitary gland (9)
and thus this would not be the case in type IA.
The absence of endogenous production of GH in IGHDIA explains the immune response upon rhGH administration; however, the appearance of antibodies may not be a regular finding even among members of the same family. Moreover, anti-GH Abs may have different binding affinities, compromising GH coupling to the receptor. GH1
mutation severity, HLA haplotypes, or other immune response genes, as well as age at first antigen contact, could contribute to these differences in immune tolerance. There have been cases of anti-GH Abs disappearing and years thereafter allowing new response to GH treatment (6)
. Interestingly, in the present case, the antibodies had persisted at a low level for many years and their levels had increased considerably after a new contact with GH. Efforts to remove anti-GH Abs with plasmapheresis or treatment with IgG or cyclophosphamide have been frustrating and nor has desensitization using small amounts of exogenous GH prevented their appearance (6)
Physiologically, GH exerts its action on the peripheral tissues both directly and indirectly with the mediation of circulating and locally produced IGF1. Severe IGHDIA with extremely low levels of circulating IGF1 could exhibit reasonable similarities with Laron's dwarfism, where a mutation in GH receptor abolishes the effect of GH on IGF1 production. Recombinant IGF1 (rhIGF1) represents an interesting treatment option for children with IGHD1A developing antibodies or GH insensitivity syndrome (7)
. rhIGF1 is not licensed for use in the treatment of adult GHD; however, in view of the very severe ‘secondary IGF1 deficiency’, it seems plausible to consider treating our patient with rhIGF1. Reports of children with type IA is quite recent and scarce (6)
and sometimes disappointing, with them not achieving a proper catch-up in growth in some cases or exhibiting secondary adverse effects on lipids and BMI.
It is well known that GHD symptoms in adulthood include changes in body composition with an increase in fat body mass in detriment of lean one, decreased bone mass, unfavorable lipid profile, reduced physical and cardiac performance, premature atherosclerosis, and poor quality of life.
BMD in short individuals measured by the standard two-dimensional method may yield false results, oversizing osteoporosis. Bone mineral apparent density (volumetric density) allows the calculation of true density, as a bone mass/volume (11)
. Thus, we calculated vertebral (L2–L4) volumetric density as bone mineral content per bone volume (area of vertebrae (cm2
)×height). Volumetric density was 0.35
, compatible with a much better bone status than obtained by areal density, although a Z
-score for his age and gender group is currently not available.
While GHD or insensitivity might be associated with hypoglycemia in children, in adults hyperglycemia is common. The age-related decline in insulin sensitivity in GH-deficient patients is not well understood yet; however, we chose to treat the patient with metformin for T2DM, as it was the most appropriate drug. Insulin resistance may be the main underlying mechanism for diabetes in our patient, after central adiposity, older age, and HOMA-IR value. Nevertheless, recent studies in Laron's dwarfs and in patients with GHRHR
gene mutation have reported normal or reduced HOMA-IR values and elevated adiponectin levels, despite concomitant obesity (12)
. Insulin secretion seems to be also compromised in the latter group after low HOMA-β levels (mean 28.1%), a value similar to that observed in the present case. It is hypothesized that significantly reduced IGF1 levels could compromise β-cell mass. In summary, IGHD would not protect from the development of diabetes as postulated.
Information on other cardiovascular risk factors in IGHD is scarce, but no premature atherosclerosis signs have been found in untreated type IB patients due to GHRHR
mutations in a Brazilian kindred (14)
. On the contrary, the patient described herein had carotid atherosclerotic plaques, indicating slow progression of atherosclerosis. This finding may well have a multifactorial origin.
Cancer reports are also anecdotic among Laron's and IGHD patients. Reduced IGF1 signaling has been reported to have a protective effect on aging in some animal models. However, this cannot be extrapolated to humans, due to a much more complex endocrine/paracrine network being involved in organ and tissue development as well as energy homeostasis throughout life. It is fairly accepted that in the post-developmental stage of life, GH and IGF1 have numerous beneficial actions in skeletal muscle and cardiovascular and nervous systems, but a negative effect on insulin sensitivity and cancer risk. There is less information on the longevity of GHDIA-affected patients, except for a report by Besson et al
. Life span was found to be greatly reduced in 11 IGHDIA individuals compared with nonaffected siblings and normal population of the same time and place (Switzerland, late 19th–early 20th century). Reported survival in GHDIA patients vs controls was 56 vs 75 years for men and 46 vs 80 years for women. The causes of death did not vary between groups: cardiovascular and infections. Of note, there were no records on cancer or diabetes, although information sources were not medical. In contrast to acquired hypopituitarism cases, congenital severe GHD cases have much lower serum IGF1 levels and have never been exposed to GH and thus they may not be equivalent in terms of GH/IGF1 axis disturbances and health prognosis.
In conclusion, establishing the etiologic diagnosis of GHD in childhood is a major challenge requiring a combination of clinical, auxological, biochemical, and pituitary imaging data. Genetic testing is recommended mainly in case of severe growth delay, familial affected members, or normal MRI, but exceptions to the rule have to be considered. This case of IGHDIA shows the persistence of anti-GH Abs 50 years after the exposure to GH and the long-lived immune intolerance despite treatment with recombinant GH preparations. Adult GH absence and the consequent severe IGF1 deficiency may underlie the patient's present metabolic disorders, osteomuscular symptoms, and reduced quality of life. However, at the moment, we choose not to treat the patient with rhIGF on the basis of risk–benefit.
IGHDIA is an exceptional in vivo model to study GH/IGF1 actions throughout life. Limitations to extending conclusions in terms of diabetes, cancer, and longevity are the few reported cases due to the rarity of the disease and the multiple in vivo biases such as particularities within endogamic kindreds or certain life styles.