Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism

Figures & data

Table 1 Physical Characteristic and Laboratory Test Results of IHH Patients

Patient No.	01	02	03	04	05	06	07	08	09	10	11
Sex	Male	Male	Male	Male	Female	Female	Male	Male	Male	Male	Male
Age (years)	17	27	16	13	31	17	20	17	16	19	17
Height (cm)	161.3	165.4	166.5	152	159	151.9	162.7	181.3	163	175.4	177
Height SDS	−1.80	−1.21	−0.82	−0.96	−0.20	−1.52	−1.67	1.48	−1.39	0.45	0.77
Weight (kg)	52.5	66.0	76.0	48.5	61.0	40.0	64.0	78.0	80.0	58.0	90.0
BMI (kg/m^2)	20.18	24.13	27.41	20.99	24.13	17.34	24.18	23.73	30.11	18.85	28.73
GH peak (ng/mL)	6.11	0.36	–	2.73	–	5.11	1.62	0.52	0.69	–	–
IGF-1 (ng/mL)	–	–	–	211	270	339	178	380	82.8	492	192
Karyotype	46XY	46XY	46XY	46XY	46XX	46XX	46XY	46XY	46XY	46XY	46XY
FSH (mIU/mL)	0.55	1.74	<0.01	0.46	3.39	0.50	0.15	0.14	<0.01	0.29	0.08
LH (mIU/mL)	<0.1	<0.1	0.11	0.07	1.43	0.42	<0.01	<0.1	<0.01	0.07	<0.01
P (ng/mL)	0.84	0.01	0.61	0.57	0.78	0.37	0.79	1.53	0.15	0.62	0.55
T (ng/mL)	0.12	0.03	0.29	0.15	0.31	0.37	0.23	1.53	0.18	0.27	0.11
PRL (IU/mL)	12.63	3.58	11.2	6.48	6.03	6.03	6.72	11.98	13.28	5.34	5.90
E2 (pg/mL)	18.05	19.41	29.68	20.84	17.63	<11.80	36.23	18.73	18.13	21.04	<11.80
FT3 (pmol/L)	5.61	–	–	6.27	5.23	5.74	–	5.28	3.64	5.57	7.01
FT4 (pmol/L)	16.80	–	–	16.80	17.4	21.23	–	15.72	15.44	18.10	15.80
TSH (mIU/mL)	1.64	–	–	1.93	3.79	1.72	–	5.28	3.83	1.45	3.29
ACTH (pmol/L) 8 am	–	3.97	5.45	3.12	3.61	9.58	10.74	9.86	3.52	8.41	6.65
ACTH (pmol/L) 4 am	–	11.00	3.43	3.00	3.27	1.89	3.20	4.63	3.84	10.38	4.78
Cortisol (ug/dL) 8 am	18.49	3.76	4.92	7.27	8.09	20.41	18.06	8.43	8.52	9.98	8.85
Cortisol (ug/dL) 4 am	19.76	11.50	2.56	6.26	3.51	10.07	7.84	3.73	9.01	11.60	3.34

Abbreviations: –, not detected; GH, growth hormone; IGF-1, insulin-like growth factor; FSH, follicle-stimulating hormone; LH, luteinizing hormone; P, progesterone; T, testosterone; PRL, prolactin; E_2, estradiol; FT3, free T3; FT4, free T4; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone.

Table 2 Clinical Phenotypes and Genetic Variants of Patients with IHH Examinated by Whole-Exome Sequencing

No.	Gene	cDNA	Protein	Zygosity	ACMG Category	Phenotype	Diagnosis (AR/AD)
02	SOX10	NM_006941.3 c.429–1G>C	IVS2	Het	LP (PVS1+PM2)	Micropenis; anosmia; low nose bridge; hearing loss; mild cubitus valgus; metacarpal sign; testicular hypotrophy	KS (AD)
	WDR11	NM_018117.11 C.2931+6delC	IVS23	Het	VUS (PM2)
04	PROKR2	NM_144773.2 c.533G>C	p.Trp 178Ser	Het	VUS (PP2+PP3+PP4)	Hyposmia; testicular hypotrophy; right olfactory-blub agenesis; sinus arrhythmia; slow growth in height; delayed puberty	KS (AD)
05	CHD7	NM_017780.3 c.3344G>A	p.Cys 1115Tyr	Het	VUS (PM1+PM2+PP3+BP1)	Anosmia; aplasia of bilateral olfactory-bulb and olfactory tract; uterine dysplasia; café-au-lait spot in the right groin	KS (AD)
06	PROKR2	NM_144773.2 c.337T>C	p.Tyr113 His	Het	VUS (PM1+PP3+BS2)	Hyposmia; uterine dysplasia; aplasia of bilateral olfactory-bulb and olfactory tract; thyroid cystic nodule; multiple nevus on the face; low hairline	KS (AD)
		NM_144773.2 c.1069C>T	p.Arg357Trp	Het	LB (BS2+BP4)
07	CHD7	NM_017780.3 c.7391A>G	p.Lys 2464Arg	Het	VUS (PM1+PM2+PP4+BP1)	Micropenis; cleft lip/palate; hearing loss; testicular hypotrophy; aplasia of bilateral olfactory-bulb	nIHH (AD)
08	PROKR2	NM_144773.2 c.533G>C	p.Trp 178Ser	Het	VUS (PP2+PP3+PP4)	Micropenis; epicanthus; cubitus valgus; sinus arrhythmia; testicular hypotrophy; aplasia of bilateral olfactory-bulb and olfactory tract	nIHH (AD)
11	FGF17	NM_003867.2 c.592G>C	p.Val 198Leu	Het	VUS (PM2)	Micropenis; anosmia; no observable sexual development	KS (AD)

Abbreviations: Het, Heterozygous; IVS, Intervening sequence; KS, Kallmann syndrome; AR, Autosomal recessive; AD, Autosomal dominance; LP, Likely pathogenic; VUS, Variant of uncertain significance.

Figure 1 Pedigree chart and genetic variants identified in patients affected with IHH.

Notes: Squares and circles indicate males and females, respectively. Numbers (01–11) represent index cases, filled symbols represent affected individuals, open symbols represent unaffected individuals. +: wild type allele; -: mutated allele; n/a: not available for genetic test; n.d.: no variants were detected. Family 1 and Family 2 denote that parental DNA samples were available. Verification of PROKR2 variant in family 1 and FGF17 variant in family 2 were performed by Sanger sequencing. The variants found in patient 06 and patient 11 were inherited from their unaffected mother.

Table 3 Genetic Variants and Clinical Outcomes of Patients Affected with KS or nIHH After Hormonal Treatment

No.	Diagnosis	Variants	Duration (Years)	Before Treatment					After Treatment
				BTV (mL)	PL (cm)	PH Tanner Stage	Breast Tanner Stage	UV (cm^3)	BTV (mL)	PL (cm)	PH Tanner Stage	Breast Tanner Stage	UV (cm^3)
01	KS	–	2.36	1.0	1.0	I	–	–	1.0	5.0	III	I	–
03	KS	–	2.49	2.0	1.5	I	I	–	3.0	6.5	IV	I	–
04	KS	PROKR2 p.W178S	3.61	1.0	1.5	I	I	–	1.0	6.0	III	–	–
06	KS	PROKR2 p.Y113H	3.46	–	–	II	II	0	–	–	II	IV	9.32
07	nIHH	CHD7 p.K2464R	0.46	0.5	3.0	–	I	–	2.0	4.0	I	–	–
08	nIHH	PROKR2 p.W178S	4.48	1.0	2.5	II	IV	–	3.0	6.0	V	IV	–
10	KS	–	1.98	2.0	2.0	III	III	–	2.0	5.0	IV	II	–

Abbreviations: –, not detected; BTV, Bilateral testicular volume; PL, Penile length; PH, Pubic hair; UV, Uterine volume.

Figure 2 Changes in testosterone, estradiol, LH and FSH levels of patients affected with IHH during therapy.

Notes: (a) serum testosterone level of male patients treated with testosterone undecanoate through the entire follow-up period; (b) serum estradiol level of female patient treated with estradiol valerate through the entire follow-up period. (c and d) Serum LH and FSH level of all patients receiving hormone treatment during the entire follow-up period.

Abbreviations: LH, luteinizing hormone; FSH, follicle-stimulating hormone.