Disorders of sex development

Then ask which developmental layer failed, when it failed, and which functions remain intact.

Think of DSD diagnosis on two axes.

The first axis is developmental layer.

Chromosomes, gonadal determination, Sertoli cell function, Leydig cell function, androgen synthesis, androgen metabolism, androgen action, target organ anatomy.

It is revealing residual pathway capacity under a new hormonal environment.

Now, consider genetics.

Modern sequencing and copy number analysis have transformed DSD diagnosis, but a negative exome does not mean the biology is undefined.

Non-coding variants, structural variation, mosaicism, and mechanisms we have not yet defined remain important.

Season 6, Episode 18, Mini-Puberty, Nature's Dynamic Test of the DSD Pathway.

A newborn with a difference of sex development gives us anatomy, but for a few months after birth, the endocrine system gives us something more valuable.

It gives us function.

Ultrasound shows a uterus.

The first question is not, which DSD syndrome is this? The first question is, where did the androgen come from? This is the framework for 46XX virilization.

Follow the androgen backward.

The external genitalia record androgen exposure.

If a uterus developed, meaningful fetal AMH exposure probably did not occur.

That shifts the problem away from testicular differentiation and toward prenatal androgen excess.

46XX testicular DSD means a testis was built.

Ovo-testicular DSD means ovarian and testicular tissues coexist.

Genetic testing then refines the map, but genetics should confirm physiology, not replace it.

Modern sequencing can identify a molecular diagnosis in a substantial fraction of 46 XY DSD cases, but not all.

Variants of uncertain significance remain common, and a gene name alone does not tell you how much enzyme activity survives.

Biochemistry still tells you what the variant did to steroid flux.

Is cortisol low? Is mineralocorticoid physiology impaired? Is blood pressure high? Which precursor accumulated? Which parallel pathway remained intact? That is how steroidogenesis becomes clinically readable.

Practice Pearl 1, under-virilization plus salt wasting localizes differently from under-virilization plus hypertension.

The adrenal phenotype is part of the DSD diagnosis.

Practice Pearl 2, a steroidogenic block changes both the missing product and the accumulated precursors.

Pathogenic variants involving AKR1C2 and AKR1C4, enzymes required for backdoor steroid metabolism, have been identified in 46 XY individuals with under-masculinized external genitalia.

If disrupting the pathway produces human DSD, the pathway contributes to normal masculinization.

POR deficiency demonstrates the opposite problem.

POR supplies electrons to several microsomal P450 enzymes.

The evidence comes from fetal tissue studies, urinary metabolomics, mechanistic enzymology, and rare genetic disorders.

That is strong evidence for the pathway's existence.

It is weaker evidence for using the pathway to explain every unexplained DSD phenotype.

use it as a framework, not as a rescue diagnosis.

For the pediatric urologist, the practical consequence is simple.

When you see severe undervirilization with testes and no uterus, do not stop at the label forty-six XY DSD.

Reconstruct the pathway.

Was AMH effective? Was testosterone produced? Did hCG stimulate testosterone? What are LH and testosterone doing at the appropriate developmental window? And can molecular testing identify the failed receptor? The answer may distinguish a testis that was poorly built from a normal target that cannot hear androgen from a Leydig compartment that cannot hear its gonadotropin signal.

Dr. McGowan is a consultant in clinical genetics at West of Scotland, Center for Genomic Medicine, and honorary clinical associate professor at the University of Glasgow.

Her key interests are inherited cardiac conditions, rare conditions, and disorders of sex development.

This is Cal.

I am joined by Drs.