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

Disclosures

J Endo Soc. 2020;4(5) 

In This Article

Case Presentation

Infancy and Childhood

The male proband was born at 41 weeks of gestation through vacuum extraction. There was no unusual exposure during pregnancy and the parents were nonconsanguineous. At birth, he was noted to have several congenital abnormalities including cleft lip and bilateral ectrodactyly of the hands and feet. Birth weight was 2724 g and height was 49.2 cm. He had a micropenis. At age 6 months, he was hospitalized to undergo surgery for repair of the cleft lip, and the preoperative laboratory tests results showed a marked hypernatremia with a serum sodium level as high as 158 mmol/L. During a water deprivation test, urine osmolarity was partially elevated with a decrease of urine volumes and unchanged serum osmolarity (Table 1). Administration of desmopressin increased urinary osmolarity, suggesting normal renal sensitivity to desmopressin. Interestingly, serum sodium levels remained as high as 160 mmol/L even after administration of desmopressin (Table 1). At age 9 months, dehydration led to severe hypernatremia (190 mmol/L). He showed refusal to feed despite hypernatremia, suggesting existence of adipsia. At that stage, he was diagnosed with essential hypernatremia by his pediatricians. The term essential hypernatremia has previously been used to describe adipsic/hypodipsic patients.[10,11] Blood test showed a low response of vasopressin to plasma osmolarity (Figure 1A).[12] Owing to the lack of sense of thirst and low secretion of vasopressin, nasal feeding and carbamazepine in infancy and desmopressin during childhood were used for water balance control. Throughout childhood, the patient suffered intermittent dehydration and poor growth (Table 2). At age 6 years, he had a supracondylar fracture of the left humerus following an accidental fall. Beyond age 10, the long-term use of desmopressin provided adequate water balance. As shown in Table 3, basal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were rather high at age 1 year. Gonadotropin-releasing hormone (GnRH) deficiency was suspected because of prolonged and low peaks of LH and FSH in response to GnRH stimulation (Table 3, middle panel). The volume of the testes was 0.5 mL at age 1 year. The volume of the testes remained as small as 0.5 to approximately 1.0 mL at age 11 years. Basal serum gonadotropin levels were low for his age at 12 years (Table 3, upper panel).

Figure 1.

Relationships of vasopressin with plasma osmolarity and one with urine osmolarity, using data obtained during years growing up. A, Correlations of urine osmolality with plasma vasopressin in normal individuals (dashed lines) and of patients with central diabetes insipidus (dotted lines). B, Correlations of urine osmolality with plasma vasopressin in normal individuals (dashed lines) and of patients with central diabetes insipidus (dotted lines). The data obtained in this work are inserted on the correlation curve made by using previous data provided by Robertson et al [12].

Adolescence and Adulthood

The patient remained relatively healthy and showed an almost normal growth curve (Table 2). However, he was diagnosed with type 2 diabetes mellitus at age 17 years. Oral glucose-lowering agents, including alogliptin (25 mg/day), an inhibitor of dipeptidyl peptidase 4, and voglibose (0.6 mg/day), an α-glucosidase inhibitor, were used to control blood glucose levels. During adulthood, he was encouraged to drink more than 1.5 L water per day to cope with adipsia, and used desmopressin nasal drops by sliding-scale, though serum sodium levels remained slightly high, ranging from 147 to 154 mmol/L. With normal activities of daily living, he graduated from the school for handicapped children and worked at a welfare workshop.

At age 31 years, he was hospitalized at NTT West Osaka Hospital (Daini Osaka Police Hospital at present) following a fracture of the left proximal femur. His orthopedic surgeon asked us to manage the patient's water-electrolyte balance. His body height and weight were 161 cm and 58 kg, respectively. Secondary sexual features, including voice changes at puberty, beard, and pubic hair, were lacking. He had a micropenis and small testes. The patient showed distinctive facial dysmorphism, including hypertelorism and a low nasal bridge (Figure 2A) with bilateral ectrodactyly of the hands and feet (Figure 2B-E). Epiphyseal fusion was noted and neurological examination showed mild hyperreflexia of bilateral upper and lower extremities with mild mental developmental delay. Brain magnetic resonance imaging (MRI) showed holoprosencephaly and olfactory bulb hypoplasia (Figure 2F and 2G). Perception of smell of flowers and food was intact, although a brain MRI showed a reduced olfactory bulb. The pituitary gland was small with absence of the posterior pituitary bright spot (Figure 2H). Based on the listed features and history, the provisional diagnosis was HS. Hormonal assays at age 31 years indicated hypogonadotropic hypogonadism (Table 3). Neither basal serum LH, basal serum FSH, nor basal serum testosterone levels were measurable. Insulin–thyrotropin-releasing hormone–GnRH challenge test showed low secretion of LH and FSH in response to GnRH, indicating hypogonadotropic hypogonadism. Other endocrinological dysfunctions such as hypothyroidism, adrenal insufficiency, and growth hormone deficiency were ruled out by evaluating multiple series of measurements of serum basal levels of hormones and clinical manifestation.

Figure 2.

A, Photograph of the 31-year-old patient with Hartsfield syndrome. Note the midface hypoplasia and repaired cleft lip; B, syndactyly of fingers; and C, split feet. D and E, Radiographs of the hands show absence of the proximal phalanges in both hands and feet. Brain magnetic resonance imaging shows F, hypoplasia of the olfactory bulb, G, partial fusion of the frontal lobes on axial image, and H, partial absence of the anterior part of the corpus callosum on the sagittal scan. Arrows indicate lesion sites. I, Sanger sequencing showing the c. 1868A > C nucleotide change in FGFR1.

During hospitalization at age 31 years, the patient was diagnosed with severe osteoporosis based on extremely low bone mineral density (BMD, 42% of average for young adult males). Other secondary osteoporosis due to endocrine disorders, gastrointestinal disorders, and autoimmune diseases was excluded by evaluating his general condition and blood examinations.[13] Then, we decided to start testosterone replacement therapy for treatment of osteoporosis. Testosterone replacement therapy gradually increased his BMD, with concomitant improvement in bone turnover markers as shown in Table 4.

Blood tests showed a low response of vasopressin to plasma osmolality (Figure 1A), and this finding was comparable for the response of central diabetes insipidus, at age 3 and confirmed at 31 years. Interestingly, urine osmolality was higher than plasma osmolarity regardless of the poor serum vasopressin secretion (Figure 1B). It is noteworthy that he had never observed polyuria during his lifetime. Daily urine volume never exceeded 3 liters. While the blood tests showed hypernatremia, urine osmolality was higher than 300 mOsm/kg. The clinical presentation and results of laboratory tests do not meet the criteria of classical form of central diabetes insipidus in this patient. Administration of desmopressin increased urinary osmolality, suggesting normal renal sensitivity to desmopressin (Table 1). While in the hospital, the patient was deprived of dosing of desmopressin under careful observation. As shown in Table 1 (lower panel), water intake (> 1.5 L/day) and restriction of daily sodium intake (< 7 g/day) were sufficient to keep serum sodium levels and urine volumes at normal levels. Although drinking another 1 L of water before sleep at night lowered urine osmolarity, it did not affect serum sodium level (which remained normal) the following morning. Based on these findings, it was concluded that desmopressin nasal drops were no longer needed. However, to fulfill the patient's desire to reduce night urination, he was discharged on oral intake of one-quarter tablet (15 μg) of desmopressin just before falling asleep. At age 32 years, cessation of oral intake of desmopressin was sometimes but not always associated with the appearance of nocturnal polyuria (900 mL/night). At the last clinical examination at our hospital at age 33 years, he was not on desmopressin with surprisingly normal serum sodium levels (138–142 mmol/L) and normal concentrated urine and free from nocturnal polyuria.

Genetic Analysis

Genomic DNA was obtained from blood cells subjected to direct Sanger sequencing of all exons in the FGFR1 gene. A novel heterozygous missense variant, NM_023110.2: c. 1868A > C (p. Asp623Ala) was detected in the FGFR1 gene. DNA samples were also obtained from the asymptomatic parents and found to lack the variant (Figure 2I). Three different amino-acid changes in the residue had previously been reported to be associated with the syndrome: Asp623Glu, Asp623Gly, and Asp623Tyr[1,3,9] (Table 5). In addition, the p. Asp623Ala variant was predicted to be disease causing by several major algorithms (PolyPhen2, SIFT, PROVEAN, PANTHER, and Mutation Taster).

Written informed consent was obtained from the patient and his parents. The institutional review board of Osaka University approved this study.

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