Most Likely Diagnosis: Autosomal Recessive Robinow Syndrome
The most likely diagnosis in a fetus presenting with severe micromelia and ambiguous genitalia with a low-risk XY cell-free DNA result is autosomal recessive Robinow syndrome, caused by biallelic mutations in ROR2. This diagnosis should be strongly considered given the characteristic triad of skeletal dysplasia with limb shortening, genital hypoplasia in a male fetus, and the absence of aneuploidy on screening 1, 2.
Diagnostic Reasoning
Why Robinow Syndrome Fits This Presentation
Severe micromelia (mesomelic limb shortening) is present in more than 75% of patients with autosomal recessive Robinow syndrome and represents a cardinal feature of this condition 1, 3.
Ambiguous genitalia/genital hypoplasia in males occurs in virtually all male patients with ROR2-related Robinow syndrome, making this a highly specific finding when combined with skeletal abnormalities 1, 4.
Low-risk XY cell-free DNA effectively excludes common aneuploidies (trisomies 13,18,21, and sex chromosome abnormalities), directing attention toward single-gene skeletal dysplasias rather than chromosomal disorders 5.
Distinguishing Features from Other Skeletal Dysplasias
The differential diagnosis for severe micromelia detected prenatally includes several lethal skeletal dysplasias, but key distinguishing features favor Robinow syndrome:
Osteogenesis imperfecta type II typically presents with undermineralized skull, beaded ribs, multiple fractures, and bone deformity—features not mentioned in this case 5.
Achondrogenesis types IA, IB, and II show profound undermineralization, absent vertebral body ossification, and barrel-shaped thorax, with detection typically at 14-16 weeks 5.
Thanatophoric dysplasia demonstrates "telephone receiver" femurs and normal mineralization, but lacks genital abnormalities 5.
Robinow syndrome uniquely combines mesomelic limb shortening with genital hypoplasia without the severe undermineralization or fractures seen in lethal skeletal dysplasias 1, 3.
Recommended Diagnostic Workup
Immediate Prenatal Evaluation
Detailed anatomical ultrasound should assess for additional features including craniofacial dysmorphisms (prominent forehead, hypertelorism, short upturned nose), vertebral anomalies (hemivertebrae, scoliosis, rib fusions), and renal anomalies 1, 3.
Femur length to abdominal circumference (FL/AC) ratio should be calculated, as ratios <0.16 suggest lethal skeletal dysplasia, while ratios >0.16 favor non-lethal conditions like Robinow syndrome 5.
Chest circumference measurements should be obtained to assess for pulmonary hypoplasia risk, though this is less commonly severe in Robinow syndrome compared to lethal skeletal dysplasias 5.
Genetic Testing Strategy
Diagnostic amniocentesis with chromosomal microarray analysis (CMA) is recommended as the next step to confirm the normal karyotype and exclude submicroscopic deletions or duplications 5.
Targeted ROR2 gene sequencing should be performed on amniotic fluid or chorionic villus sampling, looking for biallelic pathogenic variants (including both point mutations and exonic deletions) that cause autosomal recessive Robinow syndrome 1.
WNT5A sequencing should be considered if ROR2 testing is negative, as heterozygous WNT5A mutations cause autosomal dominant Robinow syndrome, though this form typically has milder skeletal findings 6, 4.
Critical Clinical Pitfalls to Avoid
Cell-Free DNA Limitations
Low-risk cell-free DNA does not exclude single-gene disorders. NIPS only screens for common aneuploidies and is not diagnostic; it cannot detect monogenic skeletal dysplasias like Robinow syndrome 5.
Sex discordance between cell-free DNA and phenotype warrants diagnostic testing, as disorders of sex differentiation can present with ambiguous genitalia in 46,XY individuals 5.
Genital Ambiguity Evaluation
Ambiguous genitalia in a 46,XY fetus requires consideration of both disorders of sex differentiation (DSD) and syndromic causes. While DSD conditions like Denys-Drash syndrome or Frasier syndrome can present with ambiguous genitalia and 46,XY karyotype, these are associated with WT1 mutations and typically include renal abnormalities (nephrotic syndrome or focal segmental glomerulosclerosis) rather than severe skeletal dysplasia 5.
Robinow syndrome causes genital hypoplasia specifically, not true gonadal dysgenesis, distinguishing it from WT1-related syndromes where gonadectomy may be indicated due to gonadoblastoma risk 5, 1.
Prognosis Assessment
Autosomal recessive Robinow syndrome is NOT typically lethal, unlike many skeletal dysplasias presenting with severe micromelia in the second trimester 1, 2, 3.
Rib fusions and vertebral anomalies (hemivertebrae, scoliosis) are present in >75% of recessive cases and help distinguish this from the milder autosomal dominant form 3.
Postnatal Management Planning
If the pregnancy continues:
Comprehensive postnatal evaluation should include skeletal radiographic survey, detailed physical examination by a geneticist, and confirmation of ROR2 mutations if not performed prenatally 5.
Multidisciplinary care coordination involving pediatric orthopedics, urology (for genital hypoplasia management), and genetics is essential 1, 2.
Genetic counseling should emphasize the 25% recurrence risk for future pregnancies given the autosomal recessive inheritance pattern 1.