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)

Abstract and Introduction

Abstract

Hartsfield syndrome (HS: OMIM 615465) is a rare congenital disease associated with a mutation of the fibroblast growth factor receptor 1 gene (FGFR1) with the main features of holoprosencephaly and ectrodactyly. Patients with HS also present with endocrinological deficits, such as isolated hypogonadotropic hypogonadism and central diabetes insipidus. Although there are several studies on infancy/childhood history, there is no study of infant/childhood/adolescent/young adult HS natural history and endocrinological findings. Here, we report a male patient with HS associated with a novel de novo FGFR1 mutation (c. 1868A > C). The endocrinological profile was evaluated at ages 1 and 31 years. This long-term follow-up study highlights functional changes in the posterior pituitary gland and features of bone metabolism disorder. We also describe the anterior pituitary function. To our knowledge this is the first description of the natural history of an HS patient through birth to young adult age. Although the HS infants reported in the literature develop central diabetes insipidus, little is known about the serial changes in pituitary gland function during growth in HS patients. In this study we describe an adult patient with HS who showed improvement of hypernatremia during early adulthood. In addition, we emphasize the importance of prevention and treatment of osteoporosis in HS.

Introduction

Hartsfield syndrome (HS) is a rare congenital disease associated with a mutation of the fibroblast growth factor receptor 1 gene (FGFR1).^[1–9] Little is known about adult HS patients and there is no study on natural history and endocrinological function in adult patients. In the present study, we report a case of a male HS patient with a novel FGFR1 mutation. We evaluated his endocrinological function both in childhood and adulthood and found interesting changes in the posterior pituitary gland and features of bone metabolism disorder.

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Abstract and Introduction
Case Presentation
Discussion
References

Table 1. Results of Water Deprivation Test and Desmopressin Challenge Tests for Evaluation of Posterior Pituitary Function. Serum Levels of Sodium and Vasopressin, Serum Osmolarity, and Urine Osmolarity After Cessation of Desmopressin Treatment
Water deprivation test
	Time, h
	0	2	6
Posm, mOsm/kg	344	339	338
Na, mmol/L	165	164	167
Uosm, mOsm/kg	235	239	337
Urine volume, mL/min	–	0.47	0.2
Body weight, g	6320	6220	6000
Desmopressin challenge test
	Age 6 mo			Age 3 y			Age 31 y
	Time, h			Time, h			Time, h
	0	3	5.5	0	1	7	0	4	6
Uosm, mOsm/kg	475	548	703	503	496	838	677	782	871
Urine volume, mL/min	–	0.19	0.06	0.67	0.29	0.12	–	0.47	0.3
Desmopressin deprivation test
	Time, d
	1	2	5^a
Na, mmol/L	155	152	153
Vasopressin, pg/mL	0.9	0.5	0.8
Posm, mOsm/kg	315	311	310
Uosm, mOsm/kg	504	677	294
Urine volume, L/d	1.2	1.1	1.5

–, not measured; upper panel: water deprivation test; middle panel: desmopressin challenge test; lower panel: serum levels of sodium and vasopressin, serum osmolarity, and urine osmolarity after cessation of desmopressin treatment. Parameters also measured on the fifth day after drinking 1 L of water just before sleep on the fourth day.
^aOn the fourth day, the patient drank 1 L of water before sleep.

Table 2. Growth Chart for Patient's Height and Weight in Childhood
Age	Height		Weight
Age	Centimeters	SD	Kilograms	SD
6 mo	64	–0.5	6.4	–1.5
9 mo	72	NA	6.59	NA
23 mo	85	–0.5	11.4	–0.5
39 mo	94.5	Mean	14	Mean
6.5 y	116	Mean	20	Mean
7.5 y	122	Mean	24	Mean
8 y	126.2	Mean	28.7	+1.0
9 y	129.5	Mean	30.75	+1.0
10 y	135	Mean	36	+1.0
11.2 y	142	Mean	42	+1.0
12 y	142	Mean	47	+1.0

Abbreviation: NA, not assessed.

Table 3. Results of Basal Hormone Levels at Ages 1, 3, 6, 12, 31, and 32 Years and Hormone Challenge Tests for Evaluation of Anterior Pituitary Function at Ages 1 and 31 Years
Assessment of basal hormones
	1 y	3 y	6 y	12 y	31 y	32 y	Reference^d
Blood glucose, mg/dL	–	88	–	–	84	88
TSH, μIL/mL	2.0	1.5	–	–	1.14	1.74	0.27–4.2
FT3, pg/mL	–	4.8	–	–	3.77	–	2.3–4.0
FT4, ng/dL	–	1.3	–	–	0.826	1.2	1.0–1.8
FSH, mIU/mL	9.1	–	0.7	1 (2.9–8.2)^a	< 0.3	< 0.3	1.5–12.4
LH, mIU/mL	17.3	–	< 0.5	< 0.5 (1.8–5.2)^b	< 0.3	< 0.3	1.7–8.6
Testosterone, ng/mL	0.28	–	0.1	–	0.23	3.4^c	1.31–8.71
PRL, ng/mL	35.6	–	3.5	–	54.5	11.8	4.3–13.7
ACTH, pg/mL	–	–	–	–	58.8	30.9	7.2–63.3
Cortisol, μg/dL	–	–	–	–	8.2	5.6	2.9–19.6
Hormone challenge test at age 1 y
	Stimulus	Time, min
	Stimulus	0	30	45	60	90	120
GH, ng/mL	Insulin	1.7	–	–	12.6	–	–
TSH, mIU/mL	TRH	2.0	–	11.2	–	–	–
LH, mIU/mL	GnRH	17.3	–	18.6	–	28.8	19.7
FSH, mIU/mL	GnRH	9.1	–	11.5	–	13.7	8.0
PRL, ng/mL	TRH	35.6	35.6	–	–	26.4	24.0
Hormone challenge test at age 31 y
	Stimulus	Time, min
	Stimulus	0	15	30	60	90	120
Blood glucose, mg/dL	Insulin, TRH, GnRH	84	65	46	64	73	74
TSH, μIL/mL		1.14	5.18	6.68	4.77	3.21	2.3
FT3, pg/mL		3.77	–	–	–	–	4.41
FT4, ng/dL		0.826	–	–	–	–	1.03
GH, ng/mL		0.25	0.23	0.85	9.68	7.6	7.13
FSH, mIU/mL		ND	ND	ND	ND	ND	ND
LH, mIU/mL		ND	0.4	0.8	1.4	1.7	2.4
PRL, ng/mL		54.5	119.1	96.2	56.8	56.6	75
ACTH, pg/mL		58.8	–	56.7	147.8	92.2	64.4
Cortisol, μg/dL		8.2	–	7.1	12.6	10.3	8.6

–; not measured.
Abbreviations: ACTH, adrenocorticotropin; FSH, follicle-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; GH, growth hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; ND, not detected; PRL, prolactin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.
^a,bReference data of the Japanese adult male when our patient was age 12 years.
^cData under testosterone replacement therapy.
^dReference data of the Japanese adult male: reference data for peak values of hormone challenge test at age 31 as follows: TSH is more than 6.0 μIU/ml, FSH increases 2 times, LH increases 5 times, PRL increases 2 times; ACTH increases 2 times, and cortisol more than 18 μg/dL.

Table 4. Results of Changes in Bone Mass and Bone Resorption/Formation Markers During Testosterone Replacement Treatment
		Treatment duration, mo				Reference
		0	2	11	33	Reference
Femur	BMD, g/cm²	0.435	0.483	0.505	0.473
	T score	–3.4	–3	–2.8	–3.1
	Z score	–3.3	–2.9	–2.8	–3
	BMC, g	2.55	2.43	2.98	2.56
Lumbar	BMD, g/cm²	0.47	0.517	0.54	0.657
	T score	–4.9	–4.5	–4.3	–3.3
	Z score	–4	–3.7	–3.5	–2.7
	BMC, g	`19.61	21.98	23.27	27.1
Bone Resorption/Formation Markers	BAP, U/L	41.3	28.5	–	12.5	3.7–20.9
	sNTx, nmolBCE/L	48.2	34.2	–	–	9.5–17.7
	TRACP-5b, mU/dL	489	357	–	133	170–590

–, not measured.
Abbreviations: BAP, bone-specific alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; sNTx, serum N-telopeptide; TRACP-5b, tartrate-resistant acid phosphatase 5b.

Table 5. Summary of Previously Reported Hartsfield Syndrome Patients
ID	Sex/Age	Genetic analysis		Affected domain	Brain imaging		Endocrinological deficiency	Follow-up	Reference
ID	Sex/Age	c. Mutation	p. Mutation	Affected domain	HPE	Pituitary	Endocrinological deficiency	Follow-up	Reference
1	M/5 y	c494T > C	p.Leu165Ser	Ig II	AL	Normal	NR	Died at age 5 y	1
2	M/4 y	c572T > C	p.Leu191Ser	Ig II	L	NR	NR	Died at age 4 y	1
3	M/14 y	c758A > C	p.His253Pro	Ig III	SL	Normal	HH	NR	5
4	M/19 y	c1029G > A	p.Ala343Ala	Ig III	L	NR	HH	Has mild intellectual disability	9
5	F/14 y	c1029G > A	p.Ala343Ala	Ig III	Abnormal corpus callosum	NR	CDI	Has mild developmental delay and intellectual disability	9
6	NR	c1454G < T	p.Gly485Val	TK	NR	NR	NR	NR	6
7	M/33 y	c1459G > T	p.Gly487Asp	TK	Abnormal corpus callosum	NR	CDI, HH, mild hypothyroidism	Resides in home with 24-h community living support staff	7
8	M/7 mo	c1460G < A	p.Gly487Asp	TK	L	NR	NR	NR	3
9	M/12 y	c1468G > C	p.Gly490Arg	TK	SL	NR	NR	Has developmental age of about 7 mo	1
10	F/NR	c1867G > T	p.Asp623Tyr	TK	L	NR	CDI, HH, normal GH secretion, low response to TRH	Mainstream school with support	1
11	M/33 y	c1868A > C	p.Asp623Ala	TK	L	No high intensity in posterior pituitary gland	HH, normal GH secretion, adipsia-hypernatremia	Works at welfare workshop	Patient in present study
12	M/7 y	c1868A > G	p.Asp623Gly	TK	SL	NR	NR	Presented with severe intellectual disability with absent speech	9
13	NR	c1869C > G	p.Asp623Glu	TK	HPE	NR	NR	NR	3
14	M/6 y	c1880G > C	p.Arg627Thr	TK	SL	NR	CDI, GH deficiency	NR	2
15	M/0Y	c1880G > C	p.Arg627Thr	TK	SL	NR	NR	NR	2
16	M/1Y	c1883A < G	p.Asn628Ser	TK	SL	NR	CDI, HH	Has tumoral calcinosis	4
17	M/19Y	c1884 T > G	p.Asn628Lys	TK	SL	Normal	CDI, HH, normal GH secretion, low response to TRH	Lives in an institution	1
18	F/11Y	c1921G > A	p.Asp641Asn	TK	SL	Hypoplasia	GH neurosecretary dysfunction, neurogenic hypernatremia	Has developmental delay	3
19	M/12Y	c1934C > T	p.Ala645Val	TK	L	NR	DI (suspected at 4 mo)→hypodipsia-hypernatremia (diagnosed at age 10 y)	NR	8
20	M/29Y	c2174 G > A	p.Cys725Tyr	TK	L	Normal	CDI, HH, normal GH secretion, low response to TRH	Works in sheltered workshop	1

Abbreviations: AL, alobar; CDI, central diabetes insipidus; DI, diabetes insipidus; F, female; GH, growth hormone; HH, hypogonadotropic hypogonadism; HPE, holoprosencephaly; ID, identification; Ig II, immunoglobulin-like 2 domain, Ig III; immunoglobulin-like 3 domain; L, lobar; M, male; NR, not reported; SL, semilobar; TK, tyrosine kinase domain; TRH, thyrotropin-releasing hormone.