Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

1.
Boehm
U
,
Bouloux
PM
,
Dattani
MT
,
de Roux
N
,
Dodé
C
,
Dunkel
L
, et al
.
Expert consensus document: european Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment
.
Nat Rev Endocrinol
.
2015
Sep
;
11
(
9
):
547
64
.
[PubMed]
1759-5029
2.
Stamou
MI
,
Cox
KH
,
Crowley
WF
Jr
.
Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the "-Omics" Era
.
Endocr Rev
.
2016
Feb
;
2016
(
1
):
4
22
.
[PubMed]
0163-769X
3.
Young
J
,
Xu
C
,
Papadakis
GE
,
Acierno
JS
,
Maione
L
,
Hietamäki
J
, et al
.
Clinical Management of Congenital Hypogonadotropic Hypogonadism.
Endocr Rev.
2019
01;40(2):669–710.
4.
Maione
L
,
Dwyer
AA
,
Francou
B
,
Guiochon-Mantel
A
,
Binart
N
,
Bouligand
J
, et al
.
GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing
.
Eur J Endocrinol
.
2018
Mar
;
178
(
3
):
R55
80
.
[PubMed]
0804-4643
5.
Pinto
G
,
Abadie
V
,
Mesnage
R
,
Blustajn
J
,
Cabrol
S
,
Amiel
J
, et al
.
CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development
.
J Clin Endocrinol Metab
.
2005
Oct
;
90
(
10
):
5621
6
.
[PubMed]
0021-972X
6.
Kim
HG
,
Kurth
I
,
Lan
F
,
Meliciani
I
,
Wenzel
W
,
Eom
SH
, et al
.
Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome
.
Am J Hum Genet
.
2008
Oct
;
83
(
4
):
511
9
.
[PubMed]
0002-9297
7.
Pingault
V
,
Bodereau
V
,
Baral
V
,
Marcos
S
,
Watanabe
Y
,
Chaoui
A
, et al
.
Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness
.
Am J Hum Genet
.
2013
May
;
92
(
5
):
707
24
.
[PubMed]
0002-9297
8.
Marcos
S
,
Sarfati
J
,
Leroy
C
,
Fouveaut
C
,
Parent
P
,
Metz
C
, et al
.
The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients
.
J Clin Endocrinol Metab
.
2014
Oct
;
99
(
10
):
E2138
43
.
[PubMed]
0021-972X
9.
Balasubramanian
R
,
Choi
JH
,
Francescatto
L
,
Willer
J
,
Horton
ER
,
Asimacopoulos
EP
, et al
.
Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency
.
Proc Natl Acad Sci USA
.
2014
Dec
;
111
(
50
):
17953
8
.
[PubMed]
0027-8424
10.
Vaaralahti
K
,
Tommiska
J
,
Tillmann
V
,
Liivak
N
,
Känsäkoski
J
,
Laitinen
EM
, et al
.
De novo SOX10 nonsense mutation in a patient with Kallmann syndrome and hearing loss
.
Pediatr Res
.
2014
Jul
;
76
(
1
):
115
6
.
[PubMed]
0031-3998
11.
Gorlin
RJ
.
Nevoid basal cell carcinoma (Gorlin) syndrome
.
Genet Med
.
2004
Nov-Dec
;
6
(
6
):
530
9
.
[PubMed]
1098-3600
12.
Kimonis
VE
,
Goldstein
AM
,
Pastakia
B
,
Yang
ML
,
Kase
R
,
DiGiovanna
JJ
, et al
.
Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome
.
Am J Med Genet
.
1997
Mar
;
69
(
3
):
299
308
.
[PubMed]
0148-7299
13.
Veenstra-Knol
HE
,
Scheewe
JH
,
van der Vlist
GJ
,
van Doorn
ME
,
Ausems
MG
.
Early recognition of basal cell naevus syndrome
.
Eur J Pediatr
.
2005
Mar
;
164
(
3
):
126
30
.
[PubMed]
0340-6199
14.
Evans
DG
,
Farndon
PA
. Nevoid Basal Cell Carcinoma Syndrome. In:
Adam
MP
,
Ardinger
HH
,
Pagon
RA
,
Wallace
SE
,
Bean
LJ
,
Stephens
K
, et al, editors
.
GeneReviews®. Seattle (WA)
.
Seattle
:
University of Washington
;
1993
.[ [cited 2018 Jun 1]], Available from http://www.ncbi.nlm.nih.gov/books/NBK1151/
15.
Gianferante
DM
,
Rotunno
M
,
Dean
M
,
Zhou
W
,
Hicks
BD
,
Wyatt
K
, et al
.
Whole-exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data
.
Mol Genet Genomic Med
.
2018
Nov
;
6
(
6
):
1168
80
.
[PubMed]
2324-9269
16.
Martinez
MF
,
Romano
MV
,
Martinez
AP
,
González
A
,
Muchnik
C
,
Stengel
FM
, et al
.
Nevoid Basal Cell Carcinoma Syndrome: PTCH1 Mutation Profile and Expression of Genes Involved in the Hedgehog Pathway in Argentinian Patients
.
Cells
.
2019
Feb
;
8
(
2
):
E144
.
[PubMed]
2073-4409
17.
Qian
H
,
Cao
P
,
Hu
M
,
Gao
S
,
Yan
N
,
Gong
X
.
Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm
.
Nat Commun
.
2019
May
;
10
(
1
):
2320
.
[PubMed]
2041-1723
18.
Pastorino
L
,
Ghiorzo
P
,
Nasti
S
,
Battistuzzi
L
,
Cusano
R
,
Marzocchi
C
, et al
.
Identification of a SUFU germline mutation in a family with Gorlin syndrome
.
Am J Med Genet A
.
2009
Jul
;
149A
(
7
):
1539
43
.
[PubMed]
1552-4825
19.
Fan
Z
,
Li
J
,
Du
J
,
Zhang
H
,
Shen
Y
,
Wang
CY
, et al
.
A missense mutation in PTCH2 underlies dominantly inherited NBCCS in a Chinese family
.
J Med Genet
.
2008
May
;
45
(
5
):
303
8
.
[PubMed]
0022-2593
20.
Lo Muzio
L
.
Nevoid basal cell carcinoma syndrome (Gorlin syndrome)
.
Orphanet J Rare Dis
.
2008
Nov
;
3
(
1
):
32
.
[PubMed]
1750-1172
21.
Lo Muzio
L
,
Nocini
PF
,
Savoia
A
,
Consolo
U
,
Procaccini
M
,
Zelante
L
, et al
.
Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals
.
Clin Genet
.
1999
Jan
;
55
(
1
):
34
40
.
[PubMed]
0009-9163
22.
Vaaralahti
K
,
Raivio
T
,
Koivu
R
,
Valanne
L
,
Laitinen
EM
,
Tommiska
J
.
Genetic Overlap between Holoprosencephaly and Kallmann Syndrome
.
Mol Syndromol
.
2012
Jun
;
3
(
1
):
1
5
.
[PubMed]
1661-8769
23.
Bree
AF
,
Shah
MR
;
BCNS Colloquium Group
.
Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS)
.
Am J Med Genet A
.
2011
Sep
;
155A
(
9
):
2091
7
.
[PubMed]
1552-4825
24.
Taylor
SF
,
Cook
AE
,
Leatherbarrow
B
.
Review of patients with basal cell nevus syndrome
.
Ophthal Plast Reconstr Surg
.
2006
Jul-Aug
;
22
(
4
):
259
65
.
[PubMed]
0740-9303
25.
Kimonis
VE
,
Mehta
SG
,
Digiovanna
JJ
,
Bale
SJ
,
Pastakia
B
.
Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome
.
Genet Med
.
2004
Nov-Dec
;
6
(
6
):
495
502
.
[PubMed]
1098-3600
26.
Cassatella
D
,
Howard
SR
,
Acierno
JS
,
Xu
C
,
Papadakis
GE
,
Santoni
FA
, et al
.
Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures
.
Eur J Endocrinol
.
2018
Apr
;
178
(
4
):
377
88
.
[PubMed]
0804-4643
27.
Maione
L
,
Benadjaoud
S
,
Eloit
C
,
Sinisi
AA
,
Colao
A
,
Chanson
P
, et al
.
Computed tomography of the anterior skull base in Kallmann syndrome reveals specific ethmoid bone abnormalities associated with olfactory bulb defects
.
J Clin Endocrinol Metab
.
2013
Mar
;
98
(
3
):
E537
46
.
[PubMed]
0021-972X
28.
Trabado
S
,
Maione
L
,
Salenave
S
,
Baron
S
,
Galland
F
,
Bry-Gauillard
H
, et al
.
Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment.
Fertil Steril.
2011
Jun;95(7):2324–9, 2329.e1-3.
29.
Maione
L
,
Fèvre
A
,
Nettore
IC
,
Manilall
A
,
Francou
B
,
Trabado
S
, et al
.
Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome
.
Hum Reprod
.
2019
Jan
;
34
(
1
):
137
47
.
[PubMed]
0268-1161
30.
Bry-Gauillard
H
,
Larrat-Ledoux
F
,
Levaillant
JM
,
Massin
N
,
Maione
L
,
Beau
I
, et al
.
Anti-Müllerian Hormone and Ovarian Morphology in Women With Isolated Hypogonadotropic Hypogonadism/Kallmann Syndrome: Effects of Recombinant Human FSH
.
J Clin Endocrinol Metab
.
2017
Apr
;
102
(
4
):
1102
11
.
[PubMed]
0021-972X
31.
Bouligand
J
,
Ghervan
C
,
Tello
JA
,
Brailly-Tabard
S
,
Salenave
S
,
Chanson
P
, et al
.
Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation
.
N Engl J Med
.
2009
Jun
;
360
(
26
):
2742
8
.
[PubMed]
0028-4793
32.
de Roux
N
,
Young
J
,
Brailly-Tabard
S
,
Misrahi
M
,
Milgrom
E
,
Schaison
G
.
The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred
.
J Clin Endocrinol Metab
.
1999
Feb
;
84
(
2
):
567
72
.
[PubMed]
0021-972X
33.
Young
J
,
Bouligand
J
,
Francou
B
,
Raffin-Sanson
ML
,
Gaillez
S
,
Jeanpierre
M
, et al
.
TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans
.
J Clin Endocrinol Metab
.
2010
May
;
95
(
5
):
2287
95
.
[PubMed]
0021-972X
34.
Soufir
N
,
Gerard
B
,
Portela
M
,
Brice
A
,
Liboutet
M
,
Saiag
P
, et al
.
PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study
.
Br J Cancer
.
2006
Aug
;
95
(
4
):
548
53
.
[PubMed]
0007-0920
35.
Posey
JE
,
Harel
T
,
Liu
P
,
Rosenfeld
JA
,
James
RA
,
Coban Akdemir
ZH
, et al
Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med.
2017
05;376(1):21–31.
36.
Ng
PC
,
Henikoff
S
.
SIFT: predicting amino acid changes that affect protein function
.
Nucleic Acids Res
.
2003
Jul
;
31
(
13
):
3812
4
.
[PubMed]
0305-1048
37.
Adzhubei
IA
,
Schmidt
S
,
Peshkin
L
,
Ramensky
VE
,
Gerasimova
A
,
Bork
P
, et al
.
A method and server for predicting damaging missense mutations
.
Nat Methods
.
2010
Apr
;
7
(
4
):
248
9
.
[PubMed]
1548-7091
38.
Richards
S
,
Aziz
N
,
Bale
S
,
Bick
D
,
Das
S
,
Gastier-Foster
J
, et al;
ACMG Laboratory Quality Assurance Committee
.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
.
Genet Med
.
2015
May
;
17
(
5
):
405
24
.
[PubMed]
1098-3600
39.
Young
J
,
Metay
C
,
Bouligand
J
,
Tou
B
,
Francou
B
,
Maione
L
, et al
.
SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development
.
Hum Reprod
.
2012
May
;
27
(
5
):
1460
5
.
[PubMed]
0268-1161
40.
Miecznikowski
JC
,
Gaile
DP
,
Liu
S
,
Shepherd
L
,
Nowak
N
.
A new normalizing algorithm for BAC CGH arrays with quality control metrics
.
J Biomed Biotechnol
.
2011
;
2011
:
860732
.
[PubMed]
1110-7243
41.
Pitteloud
N
,
Thambundit
A
,
Dwyer
AA
,
Falardeau
JL
,
Plummer
L
,
Caronia
LM
, et al
.
Role of seminiferous tubular development in determining the FSH versus LH responsiveness to GnRH in early sexual maturation
.
Neuroendocrinology
.
2009
;
90
(
3
):
260
8
.
[PubMed]
0028-3835
42.
Lindeboom
RG
,
Supek
F
,
Lehner
B
.
The rules and impact of nonsense-mediated mRNA decay in human cancers
.
Nat Genet
.
2016
Oct
;
48
(
10
):
1112
8
.
[PubMed]
1061-4036
43.
Bouligand
J
,
Delemer
B
,
Hecart
AC
,
Meduri
G
,
Viengchareun
S
,
Amazit
L
, et al
.
Familial glucocorticoid receptor haploinsufficiency by non-sense mediated mRNA decay, adrenal hyperplasia and apparent mineralocorticoid excess
.
PLoS One
.
2010
Oct
;
5
(
10
):
e13563
.
[PubMed]
1932-6203
44.
Pellegrini
C
,
Maturo
MG
,
Di Nardo
L
,
Ciciarelli
V
,
Gutiérrez García-Rodrigo
C
,
Fargnoli
MC
.
Understanding the Molecular Genetics of Basal Cell Carcinoma
.
Int J Mol Sci
.
2017
Nov
;
18
(
11
):
E2485
.
[PubMed]
1661-6596
45.
Dodé
C
,
Levilliers
J
,
Dupont
JM
,
De Paepe
A
,
Le Dû
N
,
Soussi-Yanicostas
N
, et al
.
Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome
.
Nat Genet
.
2003
Apr
;
33
(
4
):
463
5
.
[PubMed]
1061-4036
46.
Cole
LW
,
Sidis
Y
,
Zhang
C
,
Quinton
R
,
Plummer
L
,
Pignatelli
D
, et al
.
Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum
.
J Clin Endocrinol Metab
.
2008
Sep
;
93
(
9
):
3551
9
.
[PubMed]
0021-972X
47.
Salenave
S
,
Chanson
P
,
Bry
H
,
Pugeat
M
,
Cabrol
S
,
Carel
JC
, et al
.
Kallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations
.
J Clin Endocrinol Metab
.
2008
Mar
;
93
(
3
):
758
63
.
[PubMed]
0021-972X
48.
Trarbach
EB
,
Abreu
AP
,
Silveira
LF
,
Garmes
HM
,
Baptista
MT
,
Teles
MG
, et al
.
Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency
.
J Clin Endocrinol Metab
.
2010
Jul
;
95
(
7
):
3491
6
.
[PubMed]
0021-972X
49.
Ahn
SG
,
Lim
YS
,
Kim
DK
,
Kim
SG
,
Lee
SH
,
Yoon
JH
.
Nevoid basal cell carcinoma syndrome: a retrospective analysis of 33 affected Korean individuals
.
Int J Oral Maxillofac Surg
.
2004
Jul
;
33
(
5
):
458
62
.
[PubMed]
0901-5027
50.
Rayner
CR
,
Towers
JF
,
Wilson
JS
.
What is Gorlin’s syndrome? The diagnosis and management of the basal cell naevus syndrome, based on a study of thirty-seven patients
.
Br J Plast Surg
.
1977
Jan
;
30
(
1
):
62
7
.
[PubMed]
0007-1226
51.
Wallace
DC
,
Murphy
KJ
,
Kelly
L
,
Ward
WH
.
The basal cell naevus syndrome. Report of a family with anosmia and a case of hypogonadotrophic hypopituitarism
.
J Med Genet
.
1973
Mar
;
10
(
1
):
30
3
.
[PubMed]
0022-2593
52.
Marín Romero
O
,
Hernández Marín
I
,
Ayala Ruiz
AR
.
[Hypogonadism caused by Gorlin-Goltz syndrome]
.
Ginecol Obstet México
.
2006
Sep
;
74
(
9
):
493
8
.
53.
Kimonis
VE
,
Singh
KE
,
Zhong
R
,
Pastakia
B
,
Digiovanna
JJ
,
Bale
SJ
.
Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome
.
Genet Med
.
2013
Jan
;
15
(
1
):
79
83
.
[PubMed]
1098-3600
54.
Shanley
S
,
Ratcliffe
J
,
Hockey
A
,
Haan
E
,
Oley
C
,
Ravine
D
, et al
.
Nevoid basal cell carcinoma syndrome: review of 118 affected individuals
.
Am J Med Genet
.
1994
Apr
;
50
(
3
):
282
90
.
[PubMed]
0148-7299
55.
Elmaleh-Bergès
M
,
Baumann
C
,
Noël-Pétroff
N
,
Sekkal
A
,
Couloigner
V
,
Devriendt
K
, et al
.
Spectrum of temporal bone abnormalities in patients with Waardenburg syndrome and SOX10 mutations
.
AJNR Am J Neuroradiol
.
2013
Jun-Jul
;
34
(
6
):
1257
63
.
[PubMed]
0195-6108
56.
Jongmans
MC
,
van Ravenswaaij-Arts
CM
,
Pitteloud
N
,
Ogata
T
,
Sato
N
,
Claahsen-van der Grinten
HL
, et al
.
CHD7 mutations in patients initially diagnosed with Kallmann syndrome—the clinical overlap with CHARGE syndrome
.
Clin Genet
.
2009
Jan
;
75
(
1
):
65
71
.
[PubMed]
0009-9163
57.
Xu
C
,
Cassatella
D
,
van der Sloot
AM
,
Quinton
R
,
Hauschild
M
,
De Geyter
C
, et al
.
Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants
.
Genet Med
.
2018
Aug
;
20
(
8
):
872
81
.
[PubMed]
1098-3600
58.
Gonçalves
CI
,
Patriarca
FM
,
Aragüés
JM
,
Carvalho
D
,
Fonseca
F
,
Martins
S
, et al
.
High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism
.
Sci Rep
.
2019
Feb
;
9
(
1
):
1597
.
[PubMed]
2045-2322
59.
Teixeira
L
,
Guimiot
F
,
Dodé
C
,
Fallet-Bianco
C
,
Millar
RP
,
Delezoide
AL
, et al
.
Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions
.
J Clin Invest
.
2010
Oct
;
120
(
10
):
3668
72
.
[PubMed]
0021-9738
60.
Layman
WS
,
Hurd
EA
,
Martin
DM
.
Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome
.
Hum Mol Genet
.
2011
Aug
;
20
(
16
):
3138
50
.
[PubMed]
0964-6906
61.
Sweet
HO
,
Bronson
RT
,
Donahue
LR
,
Davisson
MT
.
Mesenchymal dysplasia: a recessive mutation on chromosome 13 of the mouse
.
J Hered
.
1996
Mar-Apr
;
87
(
2
):
87
95
.
[PubMed]
0022-1503
62.
Goodrich
LV
,
Milenković
L
,
Higgins
KM
,
Scott
MP
.
Altered neural cell fates and medulloblastoma in mouse patched mutants
.
Science
.
1997
Aug
;
277
(
5329
):
1109
13
.
[PubMed]
0036-8075
63.
Oro
AE
,
Higgins
K
.
Hair cycle regulation of Hedgehog signal reception
.
Dev Biol
.
2003
Mar
;
255
(
2
):
238
48
.
[PubMed]
0012-1606
64.
Sandell
LL
,
Iulianella
A
,
Melton
KR
,
Lynn
M
,
Walker
M
,
Inman
KE
, et al
.
A phenotype-driven ENU mutagenesis screen identifies novel alleles with functional roles in early mouse craniofacial development.
Genes N Y N
2000
. 2011 Apr;49(4):342–59.
65.
Feng
W
,
Choi
I
,
Clouthier
DE
,
Niswander
L
,
Williams
T
. The Ptch1(DL) mouse: a new model to study lambdoid craniosynostosis and basal cell nevus syndrome-associated skeletal defects. Genes N Y N
2000
. 2013 Oct;51(10):677–89.
66.
Hahn
LD
,
Hoyt
C
,
Rimm
DL
,
Theoharis
C
.
Spatial spectral imaging as an adjunct to the Bethesda classification of thyroid fine-needle aspiration specimens
.
Cancer Cytopathol
.
2013
Mar
;
121
(
3
):
162
7
.
[PubMed]
1934-662X
67.
Makino
S
,
Masuya
H
,
Ishijima
J
,
Yada
Y
,
Shiroishi
T
.
A spontaneous mouse mutation, mesenchymal dysplasia (mes), is caused by a deletion of the most C-terminal cytoplasmic domain of patched (ptc)
.
Dev Biol
.
2001
Nov
;
239
(
1
):
95
106
.
[PubMed]
0012-1606
68.
Metzis
V
,
Courtney
AD
,
Kerr
MC
,
Ferguson
C
,
Rondón Galeano
MC
,
Parton
RG
, et al
.
Patched1 is required in neural crest cells for the prevention of orofacial clefts
.
Hum Mol Genet
.
2013
Dec
;
22
(
24
):
5026
35
.
[PubMed]
0964-6906
69.
Kurosaka
H
,
Trainor
PA
,
Leroux-Berger
M
,
Iulianella
A
.
Cranial nerve development requires co-ordinated Shh and canonical Wnt signaling
.
PLoS One
.
2015
Mar
;
10
(
3
):
e0120821
.
[PubMed]
1932-6203
70.
Falardeau
J
,
Chung
WC
,
Beenken
A
,
Raivio
T
,
Plummer
L
,
Sidis
Y
, et al
.
Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
.
J Clin Invest
.
2008
Aug
;
118
(
8
):
2822
31
.
[PubMed]
0021-9738
71.
Kim
HG
,
Ahn
JW
,
Kurth
I
,
Ullmann
R
,
Kim
HT
,
Kulharya
A
, et al
.
WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome
.
Am J Hum Genet
.
2010
Oct
;
87
(
4
):
465
79
.
[PubMed]
0002-9297
72.
Quaynor
SD
,
Kim
HG
,
Cappello
EM
,
Williams
T
,
Chorich
LP
,
Bick
DP
, et al
.
The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome
.
Fertil Steril
.
2011
Dec
;
96
(
6
):
1424
1430.e6
.
[PubMed]
0015-0282
73.
Kim
YJ
,
Osborn
DP
,
Lee
JY
,
Araki
M
,
Araki
K
,
Mohun
T
, et al
.
WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome
.
EMBO Rep
.
2018
Feb
;
19
(
2
):
269
89
.
[PubMed]
1469-221X
74.
Quaynor
SD
,
Bosley
ME
,
Duckworth
CG
,
Porter
KR
,
Kim
SH
,
Kim
HG
, et al
.
Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome
.
Mol Cell Endocrinol
.
2016
Dec
;
437
:
86
96
.
[PubMed]
0303-7207
75.
Taroc
EZ
,
Naik
A
,
Lin
JM
,
Peterson
NB
,
Keefe
DL
Jr
,
Genis
E
, et al
.
Gli3 regulates vomeronasal neurogenesis, olfactory ensheathing cell formation and GnRH-1 neuronal migration
.
J Neurosci
.
2019
Nov
;
•••
:
1977
19
. ; [
Epub ahead of print
].
[PubMed]
0270-6474
76.
Laclef
C
,
Anselme
I
,
Besse
L
,
Catala
M
,
Palmyre
A
,
Baas
D
, et al
.
The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor
.
Hum Mol Genet
.
2015
Sep
;
24
(
17
):
4997
5014
.
[PubMed]
0964-6906
77.
Xavier
GM
,
Seppala
M
,
Barrell
W
,
Birjandi
AA
,
Geoghegan
F
,
Cobourne
MT
.
Hedgehog receptor function during craniofacial development.
Dev Biol.
2016
15;415(2):198–215.
78.
Brennan
D
,
Chen
X
,
Cheng
L
,
Mahoney
M
,
Riobo
NA
.
Noncanonical Hedgehog signaling
.
Vitam Horm
.
2012
;
88
:
55
72
.
[PubMed]
0083-6729
79.
Dhamija
R
,
Babovic-Vuksanovic
D
. Hartsfield Syndrome. In:
Adam
MP
,
Ardinger
HH
,
Pagon
RA
,
Wallace
SE
,
Bean
LJ
,
Stephens
K
, et al, editors
.
GeneReviews®. Seattle (WA)
.
Seattle
:
University of Washington
;
1993
.[ [cited 2018 Nov 9]], Available from http://www.ncbi.nlm.nih.gov/books/NBK349073/
80.
Villanueva
C
,
Jacobson-Dickman
E
,
Xu
C
,
Manouvrier
S
,
Dwyer
AA
,
Sykiotis
GP
, et al
.
Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations
.
Genet Med
.
2015
Aug
;
17
(
8
):
651
9
.
[PubMed]
1098-3600
81.
Shaw
ND
,
Brand
H
,
Kupchinsky
ZA
,
Bengani
H
,
Plummer
L
,
Jones
TI
, et al
.
SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome
.
Nat Genet
.
2017
Feb
;
49
(
2
):
238
48
.
[PubMed]
1061-4036
82.
Raivio
T
,
Avbelj
M
,
McCabe
MJ
,
Romero
CJ
,
Dwyer
AA
,
Tommiska
J
, et al
.
Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia
.
J Clin Endocrinol Metab
.
2012
Apr
;
97
(
4
):
E694
9
.
[PubMed]
0021-972X
83.
Balasubramanian
R
,
Chew
S
,
MacKinnon
SE
,
Kang
PB
,
Andrews
C
,
Chan
WM
, et al
.
Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome
.
J Clin Endocrinol Metab
.
2015
Mar
;
100
(
3
):
E473
7
.
[PubMed]
0021-972X
84.
Achermann
JC
,
Gu
WX
,
Kotlar
TJ
,
Meeks
JJ
,
Sabacan
LP
,
Seminara
SB
, et al
.
Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay
.
J Clin Endocrinol Metab
.
1999
Dec
;
84
(
12
):
4497
500
.
[PubMed]
0021-972X
85.
Margolin
DH
,
Kousi
M
,
Chan
YM
,
Lim
ET
,
Schmahmann
JD
,
Hadjivassiliou
M
, et al
.
Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination
.
N Engl J Med
.
2013
May
;
368
(
21
):
1992
2003
.
[PubMed]
0028-4793
86.
Janssen
N
,
Bergman
JE
,
Swertz
MA
,
Tranebjaerg
L
,
Lodahl
M
,
Schoots
J
, et al
.
Mutation update on the CHD7 gene involved in CHARGE syndrome
.
Hum Mutat
.
2012
Aug
;
33
(
8
):
1149
60
.
[PubMed]
1059-7794
87.
Kim
JH
,
Seo
GH
,
Kim
G-H
,
Huh
J
,
Hwang
IT
,
Jang
J-H
, et al
.
Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism.
Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc.
2018
Sep DOI: .
You do not currently have access to this content.