Growth failure in early childhood
Gene: IGFALSThe rating of this gene has been updated to GREEN following NHS Genomic Medicine Service approval.Created: 31 Jan 2023, 5:28 p.m. | Last Modified: 31 Jan 2023, 5:28 p.m.
Panel Version: 2.33
Comment on phenotypes: Previous phenotypes: Short stature;Delayed puberty;Very low IGF-I levelsCreated: 26 Mar 2024, 3:54 p.m. | Last Modified: 26 Mar 2024, 3:54 p.m.
Panel Version: 3.34
There is sufficient evidence linking biallelic variants in this gene with acid-labile subunit deficiency (MIM# 615961) characterised by IGF-I and IGFBP-3 levels, growth retardation (height, -2 to -3 SD before and during puberty) and in some also osteopenia, delayed puberty or microcephaly. However, the Endocrine Specialist Group previously determined (2019) that the phenotype was not within the scope of this panel and therefore the decision was made to classify it as Red.
Literature search revealed that in most cases growth delay becomes evident during puberty. Short stature is the presenting feature and however severity and age of onset is usually outside the scope of this clinical indication (height ≤−3 SDS at the age of at least 2 years).
Mild progressive prepubertal growth retardation has been reported in some cases which may justify the inclusion but will leave the ultimate decision with the Test Evaluation Working Group (tagged).
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- PMID: 14762184 - boy referred at 14.6 years of age with delayed and pubertal development and height −2.05 SDS. Childhood medical history unremarkable.
- PMID: 16507628 - 15.5 year old boy with height -2.1 SDS. Childhood medical history unremarkable
- PMID: 17726072 - 3 sibs with same variants. Proband at age 15.3 year had and pubertal development and height −2.00 SDS. All attained normal height by adulthood.
- PMID: 18303074 - three unrelated patients with postnatal growth deficit - P1) 4.5 years with height −2.37 SDS; P2) 4.6 years with height −3.9 SDS; P3) 15 years with height −2.54 SDS
- PMID: 23488611 - 2 sibs. Proband referred at 9 yrs of age for short stature. At 17.75 years old height was −1.9 SDS. Sisters height was −2.6 SDS at 12.3 years old.
- PMID: 24819402 - girl with height -2.9 SDS at age 3.2 years
- PMID: 27018247 - 8 unrelated cases with biallelic variants - age range: 2.4 yrs to 30.4 yrs of age; height deficit: −0.5 to −2.9 SDS. Notably, the youngest individual had the largest growth deficit.
- PMID: 30717585 - 15.25 year old boy referred for short stature (-3.04 SDS) but ultimately achieving normal height by adulthood.
- PMID: 36348166 - 7.2 year old girl with short stature (−2.14 SDS). IUGR during prenatal screening and slow but regular postnatal growth.
Heterozygous carriers also been shown to be shorter than WT relatives but with reduced penetrance (PMID: 20591980; 24356109; 24335034) and outside the scope of the panel - MOI should be biallelic only.Created: 5 Jan 2023, 12:25 p.m. | Last Modified: 5 Jan 2023, 12:25 p.m.
Panel Version: 2.10
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Acid-labile subunit, deficiency of, OMIM:615961
Publications
Review submitted on behalf of Helen Storr. Mode of inheritance: AR. Phenotypes: Growth hormone insenstivity - mild postnatal growth failure . Publications: Well established - described in 2007 and since then more than >30 cases described, likely more if screened for. A height deficit of ~1 SDS hasalso been reported in heterozygous mutation carriers. Mechansim: IGF-1 is found in circulation bound in a ternary complex with an IGFBP (predominantly IGFBP-3) and ALS. The purpose of this ternary complex is to prolong the half-life of IGF-1, but it also plays a role in regulating IGF bioavailability. ALS deficiency causes severe IGF-1 deficiency due to disruption of ternary complex (circulating IGF-1) . Penetrance: Full penetrance.Created: 22 Dec 2022, 11:07 a.m. | Last Modified: 22 Dec 2022, 11:07 a.m.
Panel Version: 2.5
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Following discussion with members of the Endocrine Specialist Group at the Webex call on 23.05.19, it was agreed that this gene was outside the scope of this clinical indication. Therefore demoted gene from Green to Red.Created: 30 May 2019, 9:49 a.m.
Phenotypes for gene: IGFALS were changed from Acid-labile subunit, deficiency of, OMIM:615961; Short stature; Delayed puberty; Very low IGF-I levels to Acid-labile subunit, deficiency of, OMIM:615961
Tag Q1_23_expert_review was removed from gene: IGFALS.
Source Expert Review Green was added to IGFALS. Source NHS GMS was added to IGFALS. Rating Changed from Red List (low evidence) to Green List (high evidence)
Publications for gene: IGFALS were set to 14762184
Tag Q1_23_expert_review tag was added to gene: IGFALS.
Phenotypes for gene: IGFALS were changed from Short stature; delayed puberty; very low IGF-I levels to Acid-labile subunit, deficiency of, OMIM:615961; Short stature; Delayed puberty; Very low IGF-I levels
Source Expert Review Red was added to IGFALS. Rating Changed from Green List (high evidence) to Red List (low evidence)
gene: IGFALS was added gene: IGFALS was added to Growth failure in early childhood. Sources: Expert Review Green Mode of inheritance for gene: IGFALS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IGFALS were set to 14762184 Phenotypes for gene: IGFALS were set to Short stature; delayed puberty; very low IGF-I levels