IHH – Acrocapitofemoral Dysplasia

Indian hedgehog (IHH) encodes a secreted signaling protein essential for endochondral ossification. Acrocapitofemoral dysplasia (acrocapitofemoral dysplasia) is a rare autosomal recessive skeletal dysplasia characterized by postnatal disproportionate short stature, short limbs, brachydactyly, cone-shaped epiphyses, narrow thorax, and relative macrocephaly. Diagnosis relies on radiographic and molecular confirmation. Inheritance is autosomal recessive with homozygous missense variants clustering in the N-terminal signaling domain.

Genome-wide homozygosity mapping in two consanguineous families linked ACFD to 2q35-q36 with a maximum two-point LOD score of 8.02 at marker D2S2248 (PMID:12632327). Five affected individuals across these families are homozygous for missense variants c.137C>T (p.Pro46Leu) and c.569T>C (p.Val190Ala), both altering conserved residues in the signaling domain. These variants segregate with disease in each pedigree, and no carriers are affected.

A third report described two adult patients from a distinct family harboring a homozygous c.478C>T (p.Arg160Cys) variant, expanding the phenotypic spectrum to include early phalangeal fusion and extreme femoral neck shortening (PMID:34530144). Radiographic progression in adulthood underscores the value of long-term follow-up in ACFD.

In a Pakistani family, whole-exome sequencing identified a novel homozygous c.518C>A (p.Ala173Asp) variant in two siblings with characteristic ACFD features. The variant segregated with disease and was absent in ethnically matched controls (PMID:40045933). This is the fourth pathogenic missense change reported and confirms allelic heterogeneity in IHH-related ACFD.

Functional modeling via in silico structural analysis and molecular dynamics simulation demonstrated that p.Ala173Asp disrupts the IHH core fold and destabilizes loop regions critical for receptor interaction, supporting a loss of signaling activity (PMID:40045933). Prior cell-based assays of analogous IHH domain mutations further corroborate impaired downstream pathway activation and chondrocyte proliferation deficits.

No conflicting evidence disputing the IHH–ACFD association has been reported. Together, these data provide strong genetic and experimental support for IHH as the causative gene in autosomal recessive acrocapitofemoral dysplasia. Key Take-home: Biallelic pathogenic IHH variants cause ACFD and should be included in targeted gene panels for skeletal dysplasia to enable precise diagnosis and family counseling.

References

• American journal of human genetics • 2003 • Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. PMID:12632327
• European journal of medical genetics • 2021 • Acrocapitofemoral dysplasia: Novel mutation in IHH in two adult patients from the third family in the literature and progression of the disease. PMID:34530144
• Molecular genetics & genomic medicine • 2025 • A Novel Biallelic Variant in IHH Causing Acrocapitofemoral Dysplasia in a Pakistani Family. PMID:40045933

Evidence Based Scoring (AI generated)