CHD7 mutations in patients initially diagnosed with Kallmann syndrome – the clinical overlap with CHARGE syndrome

Abstract

Kallmann syndrome (KS) is the combination of hypogonadotropic hypogonadism and anosmia or hyposmia, two features that are also frequently present in CHARGE syndrome. CHARGE syndrome is caused by mutations in the CHD7 gene. We performed analysis of CHD7 in 36 patients with KS and 20 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in whom mutations in KAL1, FGFR1, PROK2 and PROKR2 genes were excluded. Three of 56 KS/nIHH patients had de novo mutations in CHD7. In retrospect, these three CHD7-positive patients showed additional features that are seen in CHARGE syndrome. CHD7 mutations can be present in KS patients who have additional features that are part of the CHARGE syndrome phenotype. We did not find mutations in patients with isolated KS. These findings imply that patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, dysmorphic ears and/ or hypoplasia or aplasia of the semicircular canals, CHD7 sequencing is recommended. Keywordsanosmia; CHARGE syndrome; CHD7 gene; hypogonadotropic hypogonadism; Kallmann syndrome Kallmann syndrome (KS) is a congenital disorder that combines hypogonadotropic hypogonadism and anosmia (1). Three modes of inheritance have been described: X-linked recessive, autosomal dominant and more rarely autosomal recessive. To date, several genes have been identified to cause KS, either alone or in combination. Mutations in these genes together account for approximately 30% of all cases. KAL1 encodes the protein anosmin and

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

“…117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases. 21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3.…”

CHARGE syndrome: a review of the immunological aspects

“…FGFR1 and FGF8 (#MIM 600483) are also involved in Kallmann syndrome, which shares features such as anosmia and hypogonadotropic hypogonadism with CHARGE syndrome. 68 A common pathway for CHD7 and fibroblast growth factor 8 (FGF8)/FGFR1 has therefore been suggested. 56,69,70 FGFR1 is expressed in a subset of T-cells and is believed to interact with the T-cell receptor to enhance the activation of T-cells.…”

Clinical utility gene card for: CHARGE syndrome - update 2015

“…At the mildest end of the phenotypic spectrum, patients with CHD7 disease-causing variants may show hypogonadotropic hypogonadism with some additional minor features of CHARGE syndrome. [11][12][13] Some conditions can mimic CHARGE syndrome: 22q11.2 deletion syndrome, VACTERL association, SOX2 mutations, mandibulofacial dysostosis, chromosomal disorders (eg, deletions 3p12p21.2), 14 disorders caused by teratogens (eg, maternal diabetes, Accutane) and Kallmann syndrome. 13 …”