A 6-year-old boy is brought to the pediatric clinic with bowed legs, short stature, and dental caries. His father is similarly affected with rickets refractory to standard vitamin D therapy. On pedigree analysis, the boy's paternal grandfather is affected, but the paternal grandmother is unaffected. Notably, ALL of the paternal grandfather's daughters are affected, while NONE of his sons are affected. The structure marked **A** in the pedigree diagram represents this pathognomonic inheritance pattern. Which of the following inheritance patterns does this pedigree MOST strongly suggest?

Explanation

## Why X-linked dominant inheritance with no male-to-male transmission and 100% of daughters of affected males affected is right The pedigree pattern described—where ALL daughters of an affected male are affected but NO sons of an affected male are affected—is the pathognomonic hallmark of X-linked dominant (XLD) inheritance. This occurs because affected males carry the mutation on their single X chromosome; they pass their X to all daughters (who become affected heterozygotes) and their Y to all sons (who are unaffected). The absence of male-to-male transmission (father-to-son) is a critical distinguishing feature of XLD from autosomal dominant. In this case, the clinical diagnosis is X-linked hypophosphatemic rickets (vitamin D-resistant rickets), the most common heritable form of rickets, caused by PHEX gene mutations leading to elevated FGF23 and renal phosphate wasting. The structure marked **A**—"All Daughters of Affected Males Are Affected"—is the diagnostic signature of XLD inheritance (Nelson Pediatrics 21e Ch 99; Harrison 21e Ch 408). ## Why each distractor is wrong - **Autosomal dominant inheritance with variable penetrance and male-to-male transmission**: Autosomal dominant disorders show male-to-male transmission (affected fathers can pass the mutation to sons), which is NOT seen in this pedigree. The 100% transmission to daughters and 0% to sons is incompatible with autosomal inheritance. - **X-linked recessive inheritance with affected males and carrier females**: X-linked recessive typically presents with affected males and carrier (unaffected) females. An affected male with an X-linked recessive condition would have ALL carrier daughters (unaffected phenotypically) and all unaffected sons, not all affected daughters. This pedigree shows affected females, ruling out simple X-linked recessive. - **Autosomal recessive inheritance with consanguinity**: Autosomal recessive inheritance would require both parents to be carriers or affected. The pedigree shows unaffected individuals (paternal grandmother, paternal uncles) having unaffected children, which is inconsistent with autosomal recessive. Additionally, there is no mention of consanguinity, and the male-to-male non-transmission rules this out. **High-Yield:** X-linked dominant = NO male-to-male transmission + 100% affected daughters of affected fathers + 100% unaffected sons of affected fathers. X-linked hypophosphatemic rickets is the classic XLD example; treat with oral phosphate + calcitriol or anti-FGF23 antibody (burosumab). [cite: Nelson Pediatrics 21e Ch 99; Harrison 21e Ch 408]