Background
Case presentation
Cases
Patient 1, Family 1
Patient 1 (II:2, Family 1) | Patient 2 (II:2, Family 2) | Patient 3 (II:4, Family 2) | |
---|---|---|---|
Age, years | 7 | 11 | 2 |
Gestational age, weeks | 39 | 39 | 39 |
Birth weight, kg (SD) | 3.2 (0SD) | 3 (− 0.7SD) | 2.9 (− 0.7SD) |
Birth length, cm (SD) | 45 (−2.5SD) | NA | 46 (−1.8SD) |
Age of onset, months | 3 | 2 | 2 |
Initial manifestation hypopituitarism | + | + | + |
Basal GH μg/L (>10) | <0.2 | <0.5 | <0.5 |
TSH mU/L (0.27–4.2) | 0.02 | 0.04 | 0.4 |
PRL μg/L (2.5–15) | 0.1 | 0.1 | NA |
LH U/L (0.1–3.3) | <0.1 | <0.1 | <0.1 |
FSH U/L (0.1–7) | <0.1 | <0.1 | <0.1 |
ACTH ng/L (5–60) | 6 | 8 | 16 |
cortisol nmol/L (190–750) | 70 | 62 | 102 |
FT4 pmol/L (12–22) | 4.4 | 9.3 | 10.3 |
IGF1 ng/L (115–498) | <25 | <25 | NA |
IGFBP3 mg/L (0.7–3.6) | <0.5 | <0.3 | NA |
Hypolplastic pituitary gland | + | + | - |
Limited neck rotation | + | + | - |
SNHL | + | + | + |
Developmental delay (Mild) | + | + | + |
Other findings | Dolichocephaly, Hypolasia of facial bones, frontal bossing, short webbed neck | Dolichocephaly, Thoracic scoliosis, squint | None |
Mutation Identified | c.437G > T (p. Cys146Phe) Homozygous | c.466C > T (p. Arg156Ter) Homozygous | |
Type of mutation | Missense mutation | Nonsense | |
Effect on protein | Location a well-established domain | Null mutation | |
Computation (in silico) predictive analysis | “Damaging” | “Damaging” | |
Population data | Not annotated as polymorphism | Not annotated as polymorphism | |
Functional data | Located in functional domain | Located in functional domain | |
Allelic and family segregation data | Recessive mutation and strong segregation | Recessive mutation and strong segregation | |
Other Evidence | Relevant to patient’s phenotype | Relevant to patient’s phenotype | |
Variant classification (ACMG) | Likely pathogenic | Pathogenic |
Patient 2, Family 2
Patient 3, Family 2
Genetic analyses
Primer | Sense Strand | Antisense Strand |
---|---|---|
LHX3_Exon 1a | 5′- CAACCCAGCCAGGGAG - 3′ | 5′- GTTTCCATCTCTGTGTCCCG - 3′ |
LHX3_ Exon 1b | 5′- CCCGGAGTCGCTTGGAC - 3′ | 5′- GCCCAGATCCTCTAGCTCC - 3′ |
LHX3_ Exon 2 | 5′- CAGCCCTGAGTCCTGTGG - 3′ | 5′- TGATTGTGAGGGGAGGAGTC - 3′ |
LHX3_ Exon 3 | 5′- CGGACAGAGCCTTCCTC - 3′ | 5′- GGAGAGAATTTCCCCGGAC - 3′ |
LHX3_ Exon 4 + 5 | 5′- CTTCCGAGAAGCCTGTG - 3′ | 5′- TCCATGGGAAATTCAGATCC - 3′ |
LHX3_ Exon 6 | 5′- CTGCAGGATGGGACTCTG - 3′ | 5′- CACCAGCCCTCCCTTGAC - 3′ |
In silico prediction and pathogenicity assessment
Results
Discussion and conclusions
No. | Mutation | Amino acid change | Mutation Type | Reference | |
---|---|---|---|---|---|
Authors | Journal [Reference No] | ||||
1 | c.148A > T | Lys50Ter | Nonsense | Rajab A et al. | Hum Mol Genet 2008 [32] |
2 | c.229C > T | Arg77Ter | Nonsense | Bonfig W et al. | Eur J Pediatr 2011 [5] |
3 | c.347A > G | Tyr116Cys | Missense | Netchine I et al. | Nat Genet 2000 [29] |
4 | c.368G > A | Cys123Tyr | Missense | Sobrier M et al. | J Clin Endocrinol Metab 2012 [35] |
5 | c.437G > T | Cys146Phe | Missense | Ramzan K et al. | BMC Endocr Disord |
6 | c.466C > T | Arg156Ter | Nonsense | Ramzan K et al. | BMC Endocr Disord |
7 | c.581A > G | Gln194Arg | Missense | Bechtold-Dalla Pozza S et al. | Horm Res Paediatr 2012 [34] |
8 | c.644C > T | Ala215Val | Missense | Pfaeffle R et al. | J Clin Endocrinol Metab 2007 [31] |
9 | c.687G > A | Trp229Ter | Nonsense | Pfaeffle R et al. | J Clin Endocrinol Metab 2007 [31] |
10 | c.267-3C > G | Splicing | Sobrier M et al. | J Clin Endocrinol Metab 2012 [35] | |
11 | c.470-2 A > G | Splicing | Kristrom B et al. | J Clin Endocrinol Metab 2009 [33] | |
12 | c.111delT | Gly38Alafs*140 | Deletion | Bhangoo A et al. | J Clin Endocrinol Metab 2006 [30] |
13 | c.302_303delG CinsTCCT | Gly101Valfs*78 | Small indel | Pfaeffle R et al. | J Clin Endocrinol Metab 2007 [31] |
14 | <1.4 Mb incl. entire gene | Gross deletion | Pfaeffle R et al. | J Clin Endocrinol Metab 2007 [31] | |
15 | 23 bp E3I3-3 to E3I3 + 20 | Gross deletion | Netchine I et al. | Nat Genet 2000 [29] | |
16 | 3088 bp incl. ex. 2-5 | Gross deletion | Rajab A et al. | Hum Mol Genet 2008 [32] |