A 32-year-old man presents with short stature, bilateral cataracts (diagnosed at age 28), premature graying of hair, sclerodermatous skin changes, chronic ankle ulcers, hypogonadism, type 2 diabetes mellitus, and osteoporosis. His pedigree shows an affected sister and an unaffected brother born to unaffected parents who are first cousins. The inheritance pattern shown at position **B** in the diagram best describes this family. Which of the following is the most likely diagnosis?
A. Hutchinson-Gilford progeria syndrome (LMNA mutation, autosomal dominant)
B. Ataxia-telangiectasia (ATM gene mutation, autosomal recessive)
C. Cockayne syndrome (ERCC8/ERCC6 mutations, autosomal recessive)
D. Werner syndrome (WRN gene mutation on chromosome 8p12)
Explanation
Why Werner syndrome (WRN gene mutation on chromosome 8p12) is right
The pedigree pattern at position B — affected siblings born to unaffected consanguineous parents with no vertical transmission — is pathognomonic for autosomal recessive inheritance. Werner syndrome is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations in the WRN gene (chromosome 8p12), encoding a RecQ family DNA helicase with 3'→5' exonuclease activity. The clinical presentation is classic: onset in the 2nd–3rd decade with bilateral cataracts, scleroderma-like skin changes, premature graying, short stature, hypogonadism, type 2 diabetes, osteoporosis, and predisposition to malignancies. Parental consanguinity (first cousins) significantly increases the risk of autosomal recessive disease in offspring. The constellation of features—accelerated aging phenotype, genomic instability from impaired DNA repair and telomere maintenance, and the characteristic "bird-like" facies—is diagnostic of Werner syndrome (Oshima et al., GeneReviews — Werner Syndrome).
Why each distractor is wrong
Hutchinson-Gilford progeria syndrome: This is autosomal dominant (LMNA mutation), not recessive. It presents in infancy with severe progeria, death typically in the 2nd decade, and shows vertical transmission (affected parent to child). No parental consanguinity is required or expected.
Ataxia-telangiectasia: Although autosomal recessive, the cardinal features are cerebellar ataxia, oculomotor apraxia, telangiectasia, immunodeficiency, and radiosensitivity. Bilateral cataracts, scleroderma, hypogonadism, and type 2 diabetes are not typical. ATM encodes a DNA damage sensor, not a helicase-exonuclease.
Cockayne syndrome: Autosomal recessive (ERCC8/ERCC6 mutations), but presents with photosensitivity, progressive neurological decline, microcephaly, and retinal degeneration. Cataracts are rare, and the systemic features (hypogonadism, diabetes, osteoporosis) are not characteristic. Death typically occurs in childhood or early adulthood.
