CDH3 – Congenital Hypotrichosis with Juvenile Macular Dystrophy

Congenital hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short scalp hair from birth and progressive macular degeneration leading to blindness by the second to third decade of life. Pathogenic biallelic variants in CDH3, which encodes P-cadherin, were first identified in consanguineous families and confirmed in diverse ethnic cohorts (PMID:16120155, PMID:12445216).

The inheritance mode is autosomal recessive, with multiple consanguineous pedigrees showing complete segregation of homozygous or compound heterozygous CDH3 variants. In a large Pakistani family, six affected individuals bore a novel splice-site mutation c.1796-2A>G (p.Leu600Ter), confirming recessive transmission and intrafamilial concordance (PMID:20140736).

A series encompassing 43 probands from over 15 unrelated families has delineated the CDH3 variant spectrum (PMID:14708629, PMID:27386845, PMID:20140736). Twenty-five distinct alleles have been reported, including missense, nonsense, frameshift, splice-site, and deep intronic deletions, fulfilling criteria for strong genetic evidence.

Founder and recurrent alleles have been described: the missense R503H (c.1508G>A (p.Arg503His)) recurs in Arab Israeli families via a shared haplotype (PMID:14708629), while the splice mutation c.1796-2A>G segregates in Pakistani kindreds as a population-specific founder (PMID:20203473).

Clinical features include congenital sparse scalp hair (HP:0002209) and pigmentary macular abnormalities (HP:0008002); some patients exhibit limb anomalies such as syndactyly, reflecting phenotypic overlap with EEM syndrome. Detailed ocular imaging shows central chorioretinal atrophy and progressive outer retinal thinning (PMID:27386845, PMID:27157923).

Loss-of-function is the predominant mechanism. Truncating and splice-site mutations abolish extracellular cadherin domains, disrupting calcium-dependent cell adhesion in hair follicles and the retinal pigment epithelium. Scalp histopathology in R503H homozygotes revealed chronic telogen effluvium–like changes (PMID:15166507), and mouse in situ data demonstrate Cdh3 expression in the apical ectodermal ridge and interdigital mesenchyme, consistent with limb findings in EEM syndrome (PMID:15805154).

Functional concordance between histologic, imaging, and expression studies establishes a definitive gene-disease relationship. Given macular structural preservation early in the disease course, CDH3-targeted gene augmentation may be a viable therapeutic strategy. Key take-home: CDH3 sequencing and fundus examination are essential for diagnosing congenital hypotrichosis, enabling informed genetic counseling and potential inclusion in future gene therapy trials.

References

• The British journal of dermatology • 2005 • Molecular basis of hypotrichosis with juvenile macular dystrophy in two siblings. PMID:16120155
• Journal of investigative dermatology • 2002 • A missense mutation in CDH3, encoding P-cadherin, causes hypotrichosis with juvenile macular dystrophy. PMID:12445216
• Archives of dermatological research • 2010 • A novel splice-acceptor site mutation in CDH3 gene in a consanguineous family exhibiting hypotrichosis with juvenile macular dystrophy. PMID:20140736
• Journal of investigative dermatology • 2003 • Phenotypic diversity and mutation spectrum in hypotrichosis with juvenile macular dystrophy. PMID:14708629
• Molecular genetics & genomic medicine • 2019 • Hypotrichosis with juvenile macular dystrophy: Combination of whole-genome sequencing and genome-wide homozygosity mapping identifies a large deletion in CDH3 initially undetected by whole-exome sequencing-A lesson from next-generation sequencing. PMID:31560841
• Dermatology (Basel, Switzerland) • 2010 • Splice site mutations in the P-cadherin gene underlie hypotrichosis with juvenile macular dystrophy. PMID:20203473
• The American Journal of dermatopathology • 2004 • Histopathology of hypotrichosis with juvenile macular dystrophy. PMID:15166507
• Journal of medical genetics • 2005 • Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). PMID:15805154
• Scientific Reports • 2016 • Hypotrichosis and juvenile macular dystrophy caused by CDH3 mutation: A candidate disease for retinal gene therapy. PMID:27157923
• JAMA ophthalmology • 2016 • Characterization of CDH3-Related Congenital Hypotrichosis With Juvenile Macular Dystrophy. PMID:27386845

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