Endocrinological Features of Hartsfield Syndrome in an Adult Patient With a Novel Mutation of FGFR1

Sachiko Kobayashi; Junpei Tanigawa; Hidehito Kondo; Shin Nabatame; Azusa Maruoka; Hiroyuki Sho; Kazuko Tanikawa; Ryoko Inui; Michio Otsuki; Iichiro Shimomura; Keiichi Ozono; Kunihiko Hashimoto


J Endo Soc. 2020;4(5) 

In This Article


Although there are several observational studies on infant and childhood HS cases, little is known about adult HS patients (Table 5). This is the first report that describes the developmental outcome and endocrinological abnormalities of an adult HS patient.

The patient was found to have a novel heterozygous missense variant c. 1868A > C in FGFR1. The residue Asp623 is located in the intracellular tyrosine kinase domain, and variants in this residue have been predicted to behave as dominant negative in HS.[1,3,9] We reported here a novel heterozygous FGFR1 variant—p. Asp623Ala—and in silico analysis supported the pathogenicity of this missense variant.

FGFR1 is expressed in cranial neural crest-derived mesenchyme and involved in embryogenesis.[14,15] The FGF signaling pathway is essential for ventral telencephalon development and digit formation. FGF signals are required for the development of the olfactory bulbs[16] and gonadotropin-secreting neurons.[17] Although basal serum gonadotropin levels were rather high at age 1 year, basal serum gonadotropin and testosterone levels were low for his age at age 12 years (Table 3).[18,19] Moreover, neither basal serum LH nor basal serum FSH levels were measurable at age 31 and low response to GnRH stimulation was observed. We diagnosed him as having hypogonadotropic hypogonadism. In patients with hypogonadotropic hypogonadism, the response to the GnRH test is highly variable and depends on the severity of gonadotropin deficiency.[20] Congenital hypogonadotropic hypogonadism is often accompanied by the absence of minipuberty. One-third of congenital hypogonadotropic hypogonadism cases have partial GnRH deficiency with normal penile development and testicular descent at birth and some degree of spontaneous testicular development during adolescence. Thirteen percent of patients with Kallmann syndrome, which presents with isolated hypogonadotropic hypogonadism with anosmia, had evidence of partial puberty.[21] High basal serum levels of LH and FSH at age 1 year might suggest prolonged minipuberty with unrevealed mechanisms.[22] We speculated that gonadotropin-producing cells were alive at age 1 year, but suppression of stimulation by hypothalamic GnRH gradually attenuated the actions of gonadotrophs, with a decrease of numbers of gonadotrophs at age 31 years.

The observed hypernatremia in our patient could be explained by an inappropriate set point for vasopressin (Figure 1A). It is noteworthy that the extremely small amount of autonomic and secretory vasopressin was sufficient to regulate serum sodium levels and urine osmolarity during adulthood. We speculate that this finding is related to improvement in vasopressin sensitivity. Previous studies reported the common prevalence of diabetes insipidus in patients with HS but little is known about the pathology of posterior pituitary glands in HS (Table 5). Our patient showed adipsic hypernatremia, and vasopressin secretion was impaired. Absence of posterior pituitary hyperintensity on brain MRI suggested the existence of partial central diabetes insipidus.[23–25] But he was not diagnosed as having a classical form of central diabetes insipidus because of concentrated urine. Urine volume never exceeds 3 L per day and urine osmolarity has been rather high. The clinical scenario of only one patient resembled that of our patient (identification number 19 in Table 5). Are the endocrinological findings on the posterior pituitary gland observed in our patient commonly seen in HS? Further publications on HS may shed light and provide an answer to this question. Considering that all individuals with holoprosencephaly do not need treatment for diabetes insipidus, as described previously,[26] enhanced sensitivity to vasopressin could compensate for the lower secretion of vasopressin in patients with HS.

Unfortunately, we could not determine in this single case the exact pathophysiological mechanisms of hypernatremia and HS clinical manifestations. To date, there is no evidence for the involvement of FGFR1 in sodium reabsorption in the renal tubules, but it is possible that FGFR1 variants induce dysfunction of renal aquaporin receptors. Recently, a novel dominant-negative FGFR1 variant was found to be associated with impairment of the autophagic process.[8] FGFR1 deficiency in the renal distal tubules was also reported to be associated with cardiomegaly without affecting serum sodium concentrations.[27] Further studies are needed to determine the effect of the variant identified in FGFR1 in our patient on renal tubular function. Sodium levels are monitored in the brain and autoimmunity toward the sodium-level sensor induced adipsic (or essential) hypernatremia.[28] It is possible that yet unidentified autoantibodies to the sodium level sensor may be the culprit behind the high plasma sodium levels.

Our patient was diagnosed with diabetes mellitus as early as age 17 years. At age 31 years, his fasting blood glucose levels were as high as 198 mg/dL and the serum levels of C-peptide were 3.7 ng/mL, indicating that insulin secretion ability was still maintained. Until now, neither diabetes mellitus nor hyperlipidemia has been reported in HS patients. FGF19 and FGF21, which are FGFR1 ligands, promote energy expenditure and improve glucose metabolism.[29–31] Agonist of FGFR1 enhances thermogenesis in brown adipose tissue and is involved in weight loss and glucose and lipid metabolism.[32] The early onset diabetes mellitus in our patient might be linked to FGFR signaling in endocrine organs such as adipose tissue and liver.

The supracondylar fracture of the left humerus at age 6 years required 2 years of treatment because of delayed bone adhesion. In contrast, the fracture of the left proximal femur at age 31 healed within 1 year. It is possible that the testosterone replacement therapy during adulthood enhanced fracture healing. The treatment was designed to bring serum testosterone levels to the lower limits of normal levels, and such an approach resulted in a gradual and successful increase in BMD. These findings highlight the importance of careful monitoring of BMD and prevention of osteoporosis in adult HS.